N-substituted lactams useful as cholecystokinin antagonists

ABSTRACT

This invention relates to novel N-substituted lactams having the following formula ##STR1## useful in the treatment and prevention of Cholecystokinin (CCK) related disorders of the gastrointestinal, central nervous and appetite regulatory systems of mammals.

FIELD OF THE INVENTION

The invention herein is directed to N-substituted lactams which can beuseful in the treatment and prevention of cholecystokinin (CCK) relateddisorders of the gastrointestinal, central nervous and appetiteregulatory systems of mammals by administering to a subject in needthereof a therapeutically effective amount of a compound disclosedherein or a pharmaceutically acceptable salt thereof. Therefore, thecompounds of the invention find utility in GI motility disordersincluding irritable bowel syndrome, visceral pain, reversing satiety,and in treating anxiety. Also, the compounds of the invention are usefulin the treatment of pancreatitis and pancreatic cancer.

BACKGROUND OF THE INVENTION

Cholecystokinin (CCK) is a brain/gut neuropeptide which has beenimplicated in a number of central nervous system and gastrointestinaldisease states [Reviews: J. A. Williams, Biomedical Research (1982), 3,107; M. Albus, Prog. Neuro-Psychopharmacol & Biol. Psychiat. (1988), 12,p S5]. Cholecystokinin in the GI tract evokes contraction of gut smoothmusculature [U. Scheurer et al, Am. J. Physiol. (1983, 244, G266], andfunctionally causes delayed gastric emptying, contraction of the gallbladder [E. Corazziari et al, Dig. Dis. & Sci. (1990), 35, 50],initiation of the gastrocolic reflex [R. F. Harvey and A. E. Read, TheLancet (1973), Sat. 6 Jan., p. 7793]. CCK plays an important physiologicrole in pancreatic function and secretion. Abnormalities of CCK havebeen implicated in causing pancreatitis [C. Niederau et al,Gastroenterology (1985), 88, 1192]. Abnormalities of CCK function in theGI tract may be causitive in a number of GI motility disorders,including irritable bowel syndrome. Additionally, CCK acts as aphysiologic opiate antagonist, and has been reported to be hyperalgesic,and to inhibit analgesia produced by opiates [P. L. Faris et al, Science(1983), 219, 310; N. S. Baber et al, Pain (1989), 39, 307].

Actions of CCK in the central nervous system have demonstrated a rolefor CCK in controling eating behavior (producing satiety) [G. P. Smithin Eating and Its Disorders (A. J. Stunkard & E. Stellar, Eds), (1984),pp. 67-75, Raven Press], in producing symptoms of panic disorder & otherforms of anxiety [Trends in Pharmacol. Sci. (1990), 11, 271], and inmodulating mesolimbic dopamine release [J. N. Crawley in CholecystokininAntagonists (R. Y. Wang R. Schoenfeld, eds., (1988), pp. 243-262, AlanR. Liss].

Finally, CCK and/or gastrin have been implicated as tumorgenic in anumber of cancers, including cancers of the pancreas and the colon [S.A. Watson et al, GUT (1989, 30, 1447; B. R. Douglas et al, CancerResearch (1989), 49, 2438].

Thus, an antagonist to CCK at either the A-receptor subtype or theB-receptor subtype may be useful in the treatment of GI motilitydisorders (including irritable bowel syndrome), eating disorders wherean anti-satiety effect is desired, panic-like anxiety, compulsivebehavior and other CNS disorders.

U.S. Pat. No. 4,757,068 discloses a class of lactams and bicycliclactams which are useful in the treatment and prevention of CCK-relateddisorders of the gastrointestinal, central nervous and appetiteregulatory systems of mammals. The compounds of this disclosure arestructurally distinct from the present invention, i.e., they arebicyclic β-lactam penicillin analogs having anti-bacterial activity. Thecompounds of this disclosure are distinct from the compounds of thepresent invention both in structure and utility.

U.S. Pat. No. 3,474,093 discloses pyrrolidinone, indolinone,cycloheptapyrrolone and cyclopentapyrrolone adducts ofN-acyloxy-N-acylaminoacetanilides useful as hyperemic depressants,anti-convulsants and antiarrhythmic agents.

SUMMARY OF THE INVENTION

The present invention relates to a novel class of compounds representedby the formula ##STR2## and isomers thereof; or a pharmaceuticallyacceptable acid or base addition salt thereof:

wherein

Ar is

aryl;

substituted aryl which can be substituted one or more by alkyl of 1 to 6carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, halogen, amino, alkyl or dialkyl substituted aminowherein the alkyl is 1 to 6 carbon atoms; heterounsaturated ring having5 or 6 carbon atoms wherein one or two of the carbon atoms is replacedby nitrogen, oxygen or sulfur;

substituted heterounsaturated ring having 5 or 6 carbon atoms whereinone or two of the carbon atoms is replaced by nitrogen, oxygen or sulfurwhich can be substituted once or more by alkyl of 1 to 6 carbon atoms,halogen or trifluoromethyl; fused bicyclic aromatic hydrocarbon radicalhaving 9 or 10 carbon atoms; substituted fused bicyclic aromatichydrocarbon radical having 9 or 10 carbon atoms which can be substitutedone or more by alkyl of 1 to 6 carbon atoms, halogen, trifluoromethyl,amino, alkyl or dialkyl substituted amino wherein the alkyl is 1 to 6carbon atoms or alkoxy wherein the alkyl is 1 to 6 carbon atoms; fusedheterobicyclic hydrocarbon radical having 9 or 10 carbon atoms whereinone to three of the carbon atoms is replaced by nitrogen, oxygen orsulfur; substituted fused heterobicyclic hydrocarbon radical having 9 or10 carbon atoms wherein one to three of the carbon atoms is replaced bynitrogen oxygen or sulfur which can be substituted one or more by alkylof 1 to 6 carbon atoms, halogen, trifluoromethyl, amino, alkyl ordialkyl substituted amino wherein the alkyl is 1 to 6 carbon atoms oralkoxy wherein the alkyl is 1 to 6 carbon atoms.

R is

alkyl having 1 to 8 carbon atoms wherein one of the carbon atoms may bereplaced by oxygen;

aryl;

substituted aryl which can be substituted one or more by halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl, or methylene dioxy; aralkyl whereinthe alkyl is 1 to 8 carbon atoms; substituted aralkyl wherein the alkylis 1 to 8 carbon atoms and the substituent or substituents are selectedfrom the group consisting of halogen, alkyl having 1 to 6 carbon atoms,

alkoxy wherein the alkyl is 1 to 6 carbon atoms, amino, alkyl or dialkylsubstituted amino wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, or methylene dioxy.

X is a direct bond or a substituent selected from the group consistingof NH, oxygen or alkylene having 1 to 3 carbon atoms.

n is an integer from 0 to 1.

R₁ and R'₁ are each independently hydrogen or alkyl having 1 to 4 carbonatoms.

m is an integer from 0 to 3

R₃ is OH, OR₅ wherein R₆ is alkyl having 1 to 6 carbon atoms, NR₆ R₇wherein R₆ and R₇ are each independently hydrogen or alkyl of 1 to 6carbon atoms or NR₈ R₉ which together form a five to seven membered ringwherein R₈ and R₉ represent an alkylene group having four to six carbonatoms and one of the alkylenes may be optionally replaced by oxygen,nitrogen or NR₁₀ wherein R₁₀ represents hydrogen, or alkyl having 1 to 6carbon atoms or aralkyl wherein the alkyl is 1 to 6 carbon atoms.

R₄ is hydrogen or alkyl having 1 to 4 carbon atoms.

Y is C═O or SO₂.

The invention further relates to pharmaceutical compositions comprisinga compound of formula I. Such compounds and compositions can be usefulin the treatment and prevention of cholecystokinin (CCK) relateddisorders of the gastrointestinal, central nervous and appetiteregulatory systems.

A preferred embodiment of the present invention are compounds of theformula ##STR3## and isomers thereof; or a pharmaceutically acceptableacid or base addition salt thereof:

wherein

Ar is

aryl;

substituted aryl which can be substituted one or more by alkyl of 1 to 6carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, halogen, amino, alkyl or dialkyl substituted aminowherein the alkyl is 1 to 6 carbon atoms; heterounsaturated ring having5 or 6 carbon atoms wherein one or two of the carbon atoms is replacedby nitrogen, oxygen or sulfur; substituted heterounsaturated ring having5 or 6 carbon atoms wherein one or two of the carbon atoms is replacedby nitrogen, oxygen or sulfur which can be substituted once or more byalkyl of 1 to 6 carbon atoms, halogen or trifluoromethyl; fused bicyclicaromatic hydrocarbon radical having 9 or 10 carbon atoms; substitutedfused bicyclic aromatic hydrocarbon radical having 9 or 10 carbon atomswhich can be substituted one or more by alkyl of 1 to 6 carbon atoms,halogen, trifluoromethyl, amino, alkyl or dialkyl substituted aminowherein the alkyl is 1 to 6 carbon atoms or alkoxy wherein the alkyl is1 to 6 carbon atoms; fused heterobicyclic hydrocarbon radical having 9or 10 carbon atoms wherein one to three of the carbon atoms is replacedby nitrogen, oxygen or sulfur; substituted fused heterobicyclichydrocarbon radical having 9 or 10 carbon atoms wherein one to three ofthe carbon atoms is replaced by nitrogen oxygen or sulfur which can besubstituted one or more by alkyl of 1 to 6 carbon atoms, halogen,trifluoromethyl, amino, alkyl or dialkyl substituted amino wherein thealkyl is 1 to 6 carbon atoms or alkoxy wherein the alkyl is 1 to 6carbon atoms.

R is

alkyl having 1 to 8 carbon atoms wherein one of the carbon atoms may bereplaced by oxygen;

aryl;

substituted aryl which can be substituted one or more by halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl, or methylene dioxy; aralkyl whereinthe alkyl is 1 to 8 carbon atoms; substituted aralkyl wherein the alkylis 1 to 8 carbon atoms and the substituent or substituents are selectedfrom the group consisting of halogen, alkyl having 1 to 6 carbon atoms,alkoxy wherein the alkyl is 1 to 6 carbon atoms, amino, alkyl or dialkylsubstituted amino wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl or methylene dioxy.

X is a direct bond or a substituent selected from the group consistingof NH, oxygen or alkylene having 1 to 3 carbon atoms.

R₁ and R₁ ' are each independently hydrogen or alkyl having 1 to 4carbon atoms.

m is an integer from 0 to 3

R₃ is OH, OR₅ wherein R₅ is alkyl having 1 to 6 carbon atoms, NR₆ R₇wherein R₆ and R₇ are each independently hydrogen or alkyl of 1 to 6carbon atoms or NR₈ R₉ which together form a five to seven membered ringwherein R₈ and R₉ represent an alkylene group having four to six carbonatoms and one of the alkylenes may be optionally replaced by oxygen,nitrogen or NR₁₀ wherein R₁₀ represents hydrogen, or alkyl having 1 to 6carbon atoms or aralkyl wherein the alkyl is 1 to 6 carbon atoms.

R₄ is hydrogen or alkyl having 1 to 4 carbon atoms.

Y is C═O or SO₂.

A further preferred embodiment of the present invention are compounds ofthe formula ##STR4## and isomers thereof; or a pharmaceuticallyacceptable acid or base addition salt thereof:

wherein

Ar is

aryl;

substituted aryl which can be substituted one or more by alkyl of 1 to 6carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, halogen, amino, or alkyl or dialkyl substituted aminowherein the alkyl is 1 to 6 carbon atoms; heterounsaturated ring having5 or 6 carbon atoms wherein one or two of the carbon atoms is replacedby nitrogen, oxygen or sulfur;

substituted heterounsaturated ring having 5 or 6 carbon atoms whereinone or two of the carbon atoms is replaced by nitrogen, oxygen or sulfurwhich can be substituted once or more by alkyl of 1 to 6 carbon atoms,halogen or trifluoromethyl;

R is

alkyl having 1 to 8 carbon atoms;

aryl;

substituted aryl which can be substituted one or more by halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl or methylene dioxy or; aralkylwherein the alkyl is 1 to 8 carbon atoms.

R₁ and R₁ ' are each independently hydrogen or alkyl having 1 to 4carbon atoms.

m is an integer from 0 to 3

R₃ is OH or OR₅ wherein R₅ is alkyl having 1 to 6 carbon atoms.

R₄ is hydrogen

X is a direct bond or a substituent selected from the group consistingof NH, oxygen or alkylene having 1 to 3 carbon atoms.

Y is C═O or SO₂.

Exemplifying this embodiment are the following compounds.

cis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.

trans-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.

trans-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.

cis-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.

cis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.

cis-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

trans-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

cis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

trans-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

trans-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

cis-4-[[[3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

cis-4-[[(3,4-dichlorophenyl)sulfonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

cis-5-oxo-1-phenyl-4-[(2-pyrazinylcarbonyl)amino]-3-pyrrolidinecarboxylicacid

cis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid

cis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-(methylphenyl)-3-pyrrolidinecarboxylicacid

trans-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid

Another preferred embodiment of the present invention are compounds ofthe formula ##STR5## and isomers thereof; or a pharmaceuticallyacceptable acid or base addition salt thereof:

wherein

Ar is fused bicyclic aromatic hydrocarbon radical having 9 or 10 carbonatoms; substituted fused bicyclic aromatic hydrocarbon radical having 9or 10 carbon atoms which can be substituted one or more by alkyl of 1 to6 carbon atoms, halogen, trifluoromethyl amino, alkyl or dialkylsubstituted amino wherein the alkyl is 1 to 6 carbon atoms, or alkoxywherein the alkyl is 1 to 6 carbon atoms.

R is

alkyl having 1 to 8 carbon atoms;

aryl;

substituted aryl which can be substituted one or more by halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl, or methylene dioxy; aralkyl whereinthe alkyl is 1 to 8 carbon atoms; substituted aralkyl wherein the alkylis 1 to 8 carbon atoms and the substituent or substituents are selectedfrom the group consisting of halogen, alkyl having 1 to 6 carbon atoms,

alkoxy wherein the alkyl is 1 to 6 carbon atoms, amino, alkyl or dialkylsubstituted amino wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, or methylene dioxy;

R₁ and R₁ ' are each independently hydrogen or alkyl having 1 to 4carbon atoms.

m is an integer from 0 to 3

R₃ is OH, OR₅ wherein R₅ is alkyl having 1 to 6 carbon atoms, NR₆ R₇wherein R₆ and R₇ are each independently hydrogen or alkyl of 1 to 6carbon atoms or NR₈ R₉ which together form a five to seven membered ringwherein R₈ and R₉ represent an alkylene group having four to six carbonatoms and one of the alkylenes may be optionally replaced by oxygen,nitrogen or NR₁₀ wherein R₁₀ represents hydrogen, or alkyl having 1 to 6carbon atoms or aralkyl wherein the alkyl is 1 to 6 carbon atoms.

R₄ is hydrogen

Y is C═O or SO₂

X is a driect bond or a substituent selected from the group consistingof NH, oxygen or alkylene having 1 to 3 carbon atoms.

Exemplifying this embodiment are the following compounds:

trans-4-[(2-naphthalenylcarbonyl]amino-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.

cis-1-[(2-fluorophenyl)-4-[(2-naphthalenylcarbonyl]amino]-5-oxo-3-pyrrolidinecarboxylicacid.

cis-4-[[(2-naphthalenylamino)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.

cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

trans-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

cis-1-[[3-[(2-naphthalenylcarbonyl)amino]-2-oxo-1-phenyl-4-pyrrolidinyl]carbonyl]pyrrolidine

trans-1-[[3-[(2-naphthalenylcarbonyl)amino]-2-oxo-1-phenyl-4-pyrrolidinyl]carbonyl]pyrrolidine

trans-4-[[(2-naphthalenylamino)carbonyl]amino)-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid

1,1-dimethylethylcis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid

cis-4-[(2-naphthalenylsulfonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid

Another further preferred embodiment of the present invention arecompounds of the formula ##STR6## and isomers thereof; or apharmaceutically acceptable acid or base addition salt thereof:

wherein

Ar is fused heterobicyclic hydrocarbon radical having 9 or 10 carbonatoms wherein one to three of the carbon atoms is replaced by nitrogen,oxygen or sulfur; substituted fused heterobicyclic hydrocarbon radicalhaving 9 or 10 carbon atoms wherein one to three of the carbon atoms isreplaced by nitrogen oxygen or sulfur which can be substituted one ormore by alkyl of 1 to 6 carbon atoms, halogen, trifluoromethyl, amino,alkyl or dialkyl substituted amino wherein the alkyl is 1 to 6 carbonatoms, or alkoxy wherein the alkyl is 1 to 6 carbon atoms.

R is

alkyl having 1 to 8 carbon atoms;

aryl;

substituted aryl which can be substituted one or more by halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl, or methylene dioxy; aralkyl whereinthe alkyl is 1 to 8 carbon atoms; substituted aralkyl wherein the alkylis 1 to 8 carbon atoms and the substituent or substituents are selectedfrom the group consisting of halogen, alkyl having 1 to 6 carbon atoms,alkoxy wherein the alkyl is 1 to 6 carbon atoms, amino, alkyl or dialkylsubstituted amino wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, or methylene dioxy.

R₁ and R₁ ' are each independently hydrogen or alkyl having 1 to 4carbon atoms.

m is an integer from 0 to 3

R₃ is OH, OR₅ wherein R₅ is alkyl having 1 to 6 carbon atoms, NR₆ R₇wherein R₆ and R₇ are each independently hydrogen or alkyl of 1 to 6carbon atoms or NR₈ R₉ which together form a five to seven membered ringwherein R₈ and R₉ represent an alkylene group having four to six carbonatoms and one of the alkylenes may be optionally replaced by oxygen,nitrogen or NR₁₀ wherein R₁₀ represents hydrogen, or alkyl having 1 to 6carbon atoms or aralkyl wherein the alkyl is 1 to 6 carbon atoms.

R₄ is hydrogen

Y is C═O

X is a direct bond or a substituent selected from the group consistingof NH, oxygen or alkylene having 1 to 3 carbon atoms.

Exemplifying this embodiment are the following compounds:

trans-N-[2-oxo-1-phenyl-4-(1-pyrrolidinylcarbonyl)-3-pyrrolidinyl]-1H-indole-2-carboxamide

cis-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-1-[phenylmethyl)-3-pyrrolidinecarboxylicacid

cis-4-[(1H-indazol-3-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid

cis-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

cis-1-(2-fluorophenyl)-5-oxo-4-[(3-quinolinylcarbonyl)amino]-5-oxo-3-pyrrolidinecarboxylicacid.

trans-4[(1-H-indol-3-acetyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

cis-5-oxo-1-pentyl-4-[(3-quinolinylcarbonyl)amino]-3-pyrrolidinecarboxylicacid, monohydrochloride.

trans-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.

As used herein, the term "alkyl of 1 to 8 carbon atoms" refers tostraight chain or branched chain hydrocarbon groups having from 1 to 8carbon atoms. Illustrative of such alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl pentyl, neopentyl, hexyl, isohexyland octyl.

As used herein, the term "alkoxy wherein the alkyl is 1 to 6 carbonatoms" refers to straight or branched chain ethers. Illustrative of suchgroups are methoxy, ethoxy, propoxy, butoxy and isopropoxy.

As used herein, the term "amino" refers to the group--NH₂ ; "alkyl ordialkyl substituted amino wherein the alkyl is 1 to 6 carbon atoms"refers to the replacement of hydrogen by an alkyl group.

As used herein, the term "alkylene having 1 to 3 carbon atoms" refers tostraight or branched saturated hydrocarbon groups having from one tothree carbon atoms. Illustrative of such groups are methylene, ethylene,trimethylene, and methylethylene.

The term "aryl" represents phenyl or biphenyl.

As used herein, the term "halogen" includes fluoro, chloro and bromo.

As used herein, the term "NR₈ R₉ which together form a five to sevenmembered ring wherein R₈ and R₉ represent an alkylene group having fourto six carbon atoms and one of the alkylenes may be optionally replacedby oxygen, nitrogen or NR₁₀ wherein R₁₀ represents hydrogen, or alkylhaving 1 to 6 carbon atoms or aralkyl wherein the alkyl is 1 to 6 carbonatoms" refers to heterosaturated cyclic radical having 5 to 7 atomswherein one of the atoms in nitrogen and the remaining atoms arealkylenes wherein one of the alkylenes may be optionally replaced byoxygen, nitrogen or NR₁₀ wherein R₁₀ is defined as above. Illustrativeof such radicals are morpholinyl, pyrazolinyl, piperazinyl and 4-methylpiperizin-1-yl.

As used herein, the term "heterounsaturated ring having 5 or 6 carbonatoms wherein one or two of the carbon atoms is replaced by nitrogen,sulfur or oxygen" refers to a heterounsaturated cyclic radical having 5or 6 carbon atoms wherein one or two of the carbons is replaced bynitrogen, sulfur or oxygen. Illustrative of such radicals are pyrrolyl,imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyranyl,furanyl, thiophenyl, isothiazolyl, isoxazolyl, pyrazolinyl, andimidazolinyl, oxazolyl, and thiazolyl.

As used herein, the term "fused bicyclic aromatic hydrocarbon radicalhaving 9 or 10 carbon atoms" refers to aromatic hydrocarbons composed oftwo fused rings having a maximum number of 10 carbons. Illustrative ofsuch radicals are naphthalenyl and indenyl.

As used herein, the term "fused heterobicyclic hydrocarbon radicalhaving 9 or 10 carbon atoms wherein one to three of the carbon atoms isreplaced by nitrogen, oxygen or sulfur" refers to hydrocarbons composedof two fused rings having a maximum of i0 carbons wherein one to threeof the carbon atoms is replaced by nitrogen, oxygen or sulfur.Illustrative of such radicals are indolizinyl, isoindolyl, indolyl,indazolyl, benzofuranyl, isobenzofuranyl, chromenyl, benzothiophenyl,quinolizinyl, isoquinolinyl, quinolinyl, imidazopyridinyl,pyridinopyridinyl, phthalazinyl, naphthyridinyl, indolinyl, andchromanyl.

Included within the embodiments of the present invention are thetautomeric forms of the described compounds, isomeric forms includinggeometric isomers, enantiomers and diastereoisomers, and thepharmaceutically acceptable salts thereof.

The term "pharmaceutically-acceptable salts" embraces salts commonlyused to form alkali metal salts and to form addition salts of free acidsor free bases. Since the compounds of Formulas I, II and III containbasic nitrogen atoms, such salts are typically acid addition salts orquaternary salts. The nature of the salt is not critical, provided thatit is pharmaceutically acceptable, and acids which may be employed toform such salts are, of course, well known to those skilled in this art.Examples of acids which may be employed to form pharmaceuticallyacceptably acid addition salts include such inorganic acids ashydrochloric acid, sulphuric acid and phosphoric acid, and such organicacids as maleic acid, succinic acid and citric acid. Otherpharmaceutically acceptably salts include salts with alkali metals oralkaline earth metals, such as sodium, potassium, calcium and magnesium,or with organic bases, such as dicyclohexylamine. All of these salts maybe prepared by conventional means by reacting, for example, theappropriate acid or base with the corresponding compound of Formulas I,II and III. ##STR7##

The synthesis of compounds of Formula I wherein n equals 1 and R, R₁,R'₁, Ar, m, Y and X are defined as before and R₄ is hydrogen, R₃ is OHor OR₅ wherein R₅ is alkyl of 1 to 6 carbon atoms and (Scheme I)involves the use of methodology reported by Southwick et al. [J. Org.Chem. 21, 1087 (1956) & J. Am. Chem. Soc. 75, 3413 (1953)] for thepreparation of intermediate 2. Thus the appropriate acrylate ester 1optionally mono- or di-substituted in the beta position is reacted withthe desired aliphatic or aromatic amine (RNH₂). For an aliphatic amine,the reaction is carried out in ethanol; whereas, for an aromatic amine,the reaction is accomplished in benzene with an acid catalyst such astin tetrachloride. Subsequent reaction of the intermediate beta-aminoester species with the appropriate oxalate diester and the correspondingalkoxide followed by quenching with an acid, preferably HCl, gives thepyrrolidinone 2. The oximes 2' are formed by reaction of 2 withhydroxylamine hydrochloride in pyridine. Hydrogenation of the resultingoxime with palladium on carbon proceeds stereospecifically to give thecis-substituted aminopyrrolidinone 3. N-acylation of 3 with(hetero)arylacids by using one of several common acid-activatingreagents [CDI, DCC, SOCl₂ ] gives the amide 4 [X is direct bond or CH₂].Alternatively, treating 3 with an appropriate isocyanate orhaloformate in the presence of a base such as triethylamine affords thepyrrolidinone urea [X=NH] or urethane [X=O] 4 respectively.Saponification of the ester moiety of 4 (for R₃ =Me, Et) affords thetrans-substituted pyrrolidinone carboxylic acid 5. Alternatively estercleavage of 4 (for R₃ =tert butyl) may be accomplished with an acid,preferably trifluoroacetic acid, affording the cis-substitutedpyrrolidinone carboxylic acid 5.

The amides trans-6 and cis-6 are prepared by coupling trans-5 or cis-5,respectively, with an appropriate amine utilizing an acid-activatingagent such as carbonyldiimidazole (CDI). ##STR8##

The synthesis of homologated pyrrolidinones (m=1 to 3) of Formula Iwherein R₄ is hydrogen or alkyl (Scheme II) again relies on methodologyreported by Southwick (vide supra) for the preparation of intermediates9. Hydrolysis and decarboxylation of pyrrolidinone ester 2 proceedsunder acidic or basic conditions to give ketopyrrolidinone 9. The ketone9 may optionally be alkylated in the 4-position (R₄) by treatment with abase such as LDA and quenching with an alkylating agent R-Q such asmethyl iodide. Subsequent reaction under basic conditions with analkylating agent such as ethyl bromoacetate yields the alkylatedketopyrrolidinone 10. Formation of the oxime of ketone 10 withhydroxylamine hydrochloride in pyridine followed by hydrogenation withpalladium on carbon affords the aminopyrrolidinone 11. N-acylation of 11with (hetero)arylacids using above-described acid-activating reagentsfollowed by ester hydrolysis affords the pyrrolidinone amide 12 [X isdirect bond or CH₂ ]. Alternatively, treating 11 with an appropriateisocyanate or an appropriate haloformate in the presence of a base suchas triethylamine followed by ester hydrolysis affords the urea 12 [X=NH]or urethane 12 {X=O], respectively. The amides 13 are prepared bycoupling 12 with the appropriate amine utilizing an acid-activatingagent such as carbonyldiimidazole (CDI). ##STR9##

The synthesis of nonracemic pyrrolidinones of Formula I (Scheme III)utilizes methodology described by Dieter Enders et al. (Org. Syn. 65,183 (1987)] to form the nonracemic intermediates 11* and 11**. Thus,reaction of ketopyrrolidinone 9 with commercially-available hydrazines(S)- or (R)-1-amino-2-methoxymethylpyrrolidine (SAMP or RAMP,respectively) in benzene under Dean-Stark conditions affords thecorresponding hydrazone 14* or 14**. Reaction of each hydrazoneindividually under basic conditions with an electrophile such as ethylbromoacetate affords alkylated hydrazones 15* and 15** in highdiastereomeric excess. Removal of the hydrazone under hydrogenolysisconditions affords the cis-substituted aminopyrrolidinone 11* or 11**,depending upon the particular chiral hydrazine used. Coupling of theamines 11* and 11** followed by ester saponification proceeds as inScheme II to afford the nonracemic cis-substituted pyrrolidinone 12* and12** amides [X is a direct bond or CH₂ ], ureas [X=NH], and urethanes[X=O] as described above in Scheme II. ##STR10##

The synthesis of β-lactam of Formula I wherein n=o (Scheme IV) involvesthe use of methodology reported by T. Kawabata et al. [J. Amer. Chem.Soc. (1989), 111, 6843 & Tetrahedron Letters (1989), 30, 4837] for thepreparation of intermediates 20 and 21. Thus, the appropriate aliphaticor aromatic amine 16 is reacted sequentially witht-butylbromoacetate/triethylamine and N,N-dibenzylglycine acidchloride/triethylamine to afford the intermediates of general structure17. Dianion formation with two equivalents of alkyllithium base,followed by treatment with Cu(OAc)₂ gives predominantly thetrans-substituted azetidinone 19. Alternatively, substituting thereagent N-iodosuccinimide (NIS) in the second step affords predominatelythe cis-substituted azetidinone 18. When the amine 16 contains ahomochiral R group, the azetidinones 18 & 19 may be preparedasymmetrically.

Deprotection of the dibenzylamine moiety by hydrogenolysis gives the3-aminoazetidinones 20 and 21 from 18 and 19, respectively. N-Acylationwith (hetero)arylacids by using one of several common acid-activatingreagents [CDI, DCC, SOCl₂ ] affords the corresponding amides 22a or 23a[X is direct bond or CH₂ ]. Alternatively, treating 20 or 21 with anappropriate isocyanate affords ureas 22b or 23b [X=NH]. Alternatively,treating 20 or 21 with the appropriate haloformate gives rise tourethanes 22c or 23c [X=O]. Alternatively, treating 20 or 21 with an(hetero)aryl sulfonylchloride in the presence of base such astriethylamine gives sulfonamides of formulae 22 or 23 (Y=SO₂). Compoundsof general formulae 22 and 23 are converted to the carboxylic acids 24and 25 by treatment with an acid, preferably trifluoroacetic acid.

This invention also relates to a method of treatment and prevention ofcholecystokinin (CCK) related disorders of the gastrointestinal, centralnervous and appetite regulatory systems of mammals, and morespecifically, a method of treatment involving the administration ofcompounds of Formula I as the active ingredient.

For the treatment and prevention of CCK related disorders compounds ofFormula I may be administered orally, topically, parenterally, or byinhalation spray or rectally in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques.

The compounds of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. Therapeutically effective doses of the compounds of thepresent invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art.

Accordingly, the invention provides a class of novel pharmaceuticalcompositions comprising one or more compounds of the present inventionin association with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and if desired other active ingredients.The compounds and composition may for example be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit contained in a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. These may with advantagecontain an amount of active ingredient from about 1 to 250 mg preferablyfrom about 25 to 150 mg. A suitable daily dose for a mammal may varywidely depending on the condition of the patient and other factors.However, a dose of from about 0.1 to 3000 mg/kg body weight,particularly from about 1 to 100 mg/kg body weight may be appropriate.

The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight.

The dosage regimen for treating an infectious disease condition with thecompounds and/or compositions of this invention is selected inaccordance with a variety of factors, including the type, age, weight,sex and medical condition of the patient; the severity of the infection;the route of administration; and the particular compound employed andthus may vary widely.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If per os, the compounds may be admixed with lactose,sucrose, starch powder, cellulose esters of alkanoic acids, cellulosealkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide,sodium and calcium salts of phosphoric and sulphuric acids, gelatin,acacia, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol,and thus tableted or encapsulated for convenient administration.Alternatively, the compounds may be dissolved in water, polyethyleneglycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art. Appropriate dosages, in any given instance, ofcourse depend upon the nature and severity of the condition treated, theroute of administration, and the species of mammal involved, includingits size and any individual idiosyncrasies.

Representative carriers, diluents and adjuvants include for example,water, lactose, gelatin, starches, magnesium stearate, talc, vegetableoils, gums, polyalkylene glycols, petroleum jelly, etc. Thepharmaceutical compositions may be made up in a solid form such asgranules, powders or suppositories or in a liquid form such assolutions, suspensions or emulsions. The pharmaceutical compositions maybe subjected to conventional pharmaceutical operations such assterilization and/or may contain conventional pharmaceutical adjuvantssuch as preservatives, stabilizers, wetting agents, emulsifiers,buffers, etc.

Dosage levels of the order from about 0.01 mg to about 10 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (from about 10 mg to about 1000 mg perpatient per day).

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of subjects may containfrom 5 mg to 1.0 g of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 to 95percent of the total composition. Dosage unit forms will generallycontain between from about 25 mg to about 500 mg of active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following Examples are intended to further illustrate the presentinvention and not to limit the invention in spirit or scope. In theExamples, all parts are parts by weight unless otherwise expressly setforth.

Preparation of Starting Materials Example A Preparation of Ethyl3-(phenylamino)propanoate

According to the procedure of P. L. Southwick, J. Am. Chem. Soc. 75 3413(1953), to a solution of aniline (31.86 g, 0.35 mol) and ethyl acrylate(35.0 g, 0.35 mol) in 200 ml of dry benzene (freshly distilled fromCaH₂) was added 0.5 ml of tin tetrachloride and the resulting solutionwas heated under reflux for 24 h. After cooling to room temperature thesuspension was filtered to remove the inorganic solids and thenconcentrated in vacuo to give a dark green oil which was chromatographedon silica gel eluting with ethyl acetate/toluene (30/70) to give thetitle compound (40.7 g, 60%) as a light yellow oil. B.p. 95°-98° C. at0.1 mm Hg.

Example B Preparation of 1,1-Dimethylethyl 3-(phenylamino)propanoate

To a solution of aniline (27.9 g, 0.30 mol) and tert-butyl acrylate(38.4 g, 0.30 mol) in dry benzene (500 ml) was added tin tetrachloride(2 ml) and the resulting solution was heated under reflux for 18 h. Theresulting suspension was filtered and the filtrate was concentrated invacuo giving a residue which was chromatographed on silica gel elutingwith 25/75 ethyl acetate/hexane to give the title compound (22.53 g,34%) as an oil. ¹ H NMR (300 MHz, CDCl₃) δ7.12 (2H, t), 6.71 (1H, m),6.62 (2H, d), 3.40 (2H, t), 2 54 (2H, t), 1.44 (9H, s).

Example C Preparation of 1,1-Dimethylethyl3-[(2-fluorophenyl)amino]propanoate

To a solution of 2-fluoroaniline (22.06 g, 0.198 mol) and freshlydistilled tert-butyl acrylate (25.145 g, 0.198 mol) in dry benzene (250ml) was added tin tetrachloride (1 ml) and the mixture was refluxed for60 h. The resulting suspension was filtered and the filtrate wasevaporated to give a semisolid which was chromatographed on silica geleluting with 25/75 ethyl acetate/hexane to give the title compound (5.4g, 11%). Anal calcd for C₁₃ H₁₈ NO₂ F: C, 65.25; H, 7.58; N, 5.85.Found: C, 65.49; H, 7.75; N, 5.80. MS M+1 calcd for C₁₃ H₁₈ NO₂ F 240,found 240.

Example D Preparation of Ethyl2,5-dihydro-4-hydroxy-5-oxo-1-pentyl-1H-pyrrole-3-carboxylate

The title compound was prepared by the general method of Southwick [J.Org. Chem. 21, 1087 (1956)]. Thus to a solution of n-pentylamine (8.04g, 92.3 mmol) in 50 ml of dry EtOH was added ethyl acrylate (9.24 g,92.3 mmol) with stirring under nitrogen at room temperature. After 18 hat room temperature, diethyl oxalate (13.5 g, 92.3 mmol) was addedfollowed by a solution of sodium ethoxide in EtOH [made from sodium(2.12 g, 92.3 mmol) in 50 ml of dry EtOH]. The reaction mixture was thenheated under reflux for 1 hour. To the resulting suspension was added150 ml H₂ O and the reaction mixture was then concentrated under astream of nitrogen to remove the EtOH. The white solid was thendissolved in 200 ml H₂ O and the solution was acidified withconcentrated aqueous HCl (8.9 ml of a 10.4N solution). The resultingcrystals were filtered, washed with water and dried to give the titlecompound (15.9 g, 71.4%) as colorless plates: mp 122°-123° C. Anal calcdfor C₁₂ H₁₉ NO₄ : C, 59.74; H, 7.94; N, 5.80. Found: C, 59.46; H, 7.87;N, 5.83.

Example E Preparation of Ethyl2,5-dihydro-4-hydroxy-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate

The title compound was prepared as described by Southwick in J. Am.Chem. Soc. 75 3413 (1953). Thus to a solution of ethyl2-phenylaminopropionate (40.7 g, 0.211 mol) and diethyl oxylate (30.8 g,0.211 mol) in EtOH (250 ml, freshly distilled from Na) cooled to -3° C.was added via cannula a solution of sodium ethoxide in EtOH freshly madefrom 280 ml EtOH and sodium (4.85 g, 0.211 mol). The temperature wasmaintained below 5° C. throughout the addition. After the addition wascomplete the solution was allowed to warm to room temperature andstirring was continued overnight. The resulting slurry was acidifiedwith 15% HCl to pH=2 and the resulting precipitate was filtered to givethe title compound

(29.3 g, 56%) as a colorless powder. Calcd for C₁₃ H₁₃ NO₄ : C, 63.15;H, 5.30; N, 5.66. Found C, 62.68; H, 5.31; N, 5.55. DSC=155.98°-158.33°C. at 130.5 J/g.

Example F Preparation of 1,1-Dimethylethyl2,5-dihydro-4-hydroxy-5-oxo-1-pentyl-1H-pyrrole-3-carboxylate

To a solution of n-pentyl amine (21.72 g, 0.25 mol) in 110 ml of EtOH(freshly distilled from sodium) was added tert-butyl acrylate (36.62 ml,0.26 mol) via syringe and the resulting solution was stirred under anatmosphere of argon for 12 h at room temperature. To the solution wasthen added diethyl oxalate (36.54 g, 0.25 mol). The solution was thencooled to 0° C. and a freshly prepared solution of sodium ethoxide (from5.75 g (0.25 mole) of sodium and 75 ml of EtOH) was added via cannulawhile maintaining the temperature between 0° C. and 5° C. After theaddition was complete, the solution was allowed to warm to roomtemperature and stirred overnight. To the resulting slurry was added 400ml of water followed the slow addition of 30% aqueous HCl to acidify topH=4. The suspension was then extracted with CH₂ Cl₂. The organic phasewas dried over MgSO₄, filtered, and concentrated in vacuo to give awhite solid. Recrystallization from ethyl acetate was dried gave thetitle compound (31.57 g, 47%) as a colorless powder. Anal calcd for C₁₄H₂₃ NO₄ 1/4H₂ O: C, 61.40; H, 8.65; N, 5.11. Found: C, 61.38; H, 8.54;N, 5.22. MS M+1 calcd for C₁₄ H₂₃ NO₄ 270, found 270. DSC=102.3°-106.4°C. at 101.7 J/g. Chromatography of the mother liquor on silica geleluting with EtOH/CH₂ Cl₂ /HOAc (2/98/1) gave an additional 17.5 g (26%)of the title compound.

Example G Preparation of 1,1-Dimethylethyl2,5-dihydro-4-hydroxy-5-oxo-1-phenyl-1H-pyrrole-3-carboxylate

To a solution of the title compound of Example B (29.37 g, 0.133 mol)and di-tert-butyl oxalate (26.90 g, 0.133 mol) in dry THF (350 ml) wasadded potassium tert-butoxide (29.84 g, 0.266 mol) and the resultingsolution was heated under reflux for 24 h. The mixture was then cooledand the solvent removed in vacuo. The resulting solid was suspended inCH₂ Cl₂ and 1N aqueous HCl was added. The resulting suspension wasfiltered and the organic filtrate was dried over MgSO₄ and concentratedin vacuo. The residue was then chromatographed on silica gel elutingwith 1/1/98 HOAc/EtOH/CH₂ Cl₂ to give the title compound (19.06 g, 52%)as a solid. Anal calcd for C₁₅ H₁₇ NO₄ : C, 65.44; H, 6.22; N, 5.09.Found: C, 65.05; H, 6.33; N, 4.86. MS M+1 calcd for C₁₅ H₁₇ NO₄ 276,found 276.

Example H Preparation of 1,1-Dimethylethyl1-(2-fluorophenyl)-2,5-dihydro-4-hydroxy-5-oxo-1H-pyrrole-3-carboxylate

To a solution of the title compound of Example C (5.41 g, 22.6 mmol) indry THF (100 ml) was added di-tert-butyl oxalate (4.57 g, 22.6 mmol),followed by potassium tert-butoxide (5.07 g, 45.2 mmol) and theresulting dark yellow solution was stirred for 84 h at room temperature.The reaction mixture was then acidified with 1N HCl to pH=3, followed bythe addition of H₂ O (35 ml) and the mixture was then extracted with CH₂Cl₂. The combined organic layers were dried with MgSO₄, filtered anddried to give a solid which was chromatographed on silica gel elutingwith 1/1/98 MeOH/HOAc/CH₂ Cl₂ to give the title Compound (3.166 g, 48%).Anal calcd for C₁₅ H₁₆ NO₄ F: C, 61.43; H, 5.50; N, 4.78. Found: C,61.16; H, 5.50; N, 4.77.

Example I Preparation of 1,1-Dimethylethyl2,5-dihydro-4-hydroxy-5-oxo-1-(phenylmethyl)-1H-pyrrole-3-carboxylate

To a solution of benzyl amine (7.3 ml, 0.067 mol) in dry EtOH (freshlydistilled from sodium) was added tert-butyl acrylate (6.8 ml, 0.046 mol)via syringe and the resulting solution was stirred under an atmosphereof argon for 64 h at room temperature. To the solution was then addeddiethyl oxalate (9.90 g, 0.068 mol). The solution was then cooled to 0°C. and a freshly prepared solution of sodium ethoxide [freshly preparedfrom sodium (1.7 g, 0.074 mol) and 75 ml of EtOH] was added via cannulawhile maintaining the temperature between 0° C. and 5° C. After theaddition was complete the solution was warmed to room temperature andstirred overnight. To the resulting slurry was added 100 ml of waterfollowed by the slow addition of 30% aqueous HCl to acidify to pH=1. Thesuspension was then extracted with CH₂ Cl₂. The organic phase was driedover MgSO₄, filtered, and concentrated in vacuo to give the titlecompound as a light pink powder (8.37 g, 62.9%). Purification of ananalytical sample by chromatography on silica gel eluting with5/94.5/0.5 MeOH/CH₂ Cl₂ /HOAc gave 8.67g, (65%) of the title compound asa powder. Anal calcd for C₁₆ H₁₉ NO₄ : C, 66.43; H, 6.52; N, 4.84.Found: C, 66.38; H, 6.70; N, 5.10. DSC=172.2°-176.2° at 190.9 J/g.

Example J Preparation of Ethyl2,5-dihydro-4-hydroxy-2-methyl-5-oxo-1-pentyl-1H-pyrrole-3-carboxylate

To a solution of n-pentyl amine (28.98 ml, 0.25 mol) in absolute EtOH(110 ml) was added ethyl crotonate (31.1 ml, 0.25 mol) and the solutionwas stirred for 16 h at room temperature. To the clear solution was thenadded diethyl oxalate (33.95 ml, 0.25 mol) followed by a solution ofsodium ethoxide [freshly prepared from sodium (5.75 g, 0.25 mol) and 75ml of absolute EtOH]. After stirring for 16 h at room temperature, thesolvent was removed in vacuo to give an orange oil. Water was added tothe oil followed by 1N HCl to acidify to pH=3, and the mixture was thenextracted with CH₂ Cl₂ (3×500 ml). The combined organic layers werewashed with water and brine and then concentrated in vacuo to give anoil which was chromatographed on silica gel eluting with 10/89/1EtOH/CH₂ Cl₂ /HOAc to give the title compound (21.88 g, 34%) as a pinksolid. DSC=37.8°-44.3° C. at 63.9 J/g.

Example K Preparation of Ethyl4-(hydroxyimino)-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To a solution of the title compound of Example D (5.0 g, 20.2 mmol) in50 ml of pyridine was added hydroxylamine hydrochloride (1.58 g, 24.2mmol) and the solution was stirred for 16 h at room temperature.Concentration in vacuo gave an oil which was chromatographed on silicagel eluting with EtOH/CH₂ Cl₂ (10/90) to give the title compound (5.18g, 98%) as a colorless solid. MS calcd for C₁₂ H₂₀ N₂ O₄ 256, found 256.

Example L Preparation of Ethyl4-(hydroxyimino)-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a mechanically stirred solution of the title compound of Example E(21 g, 0.085 mol) in 450 ml of pyridine was added hydroxylaminehydrochloride (8.83 g, 0.127 mol). After stirring for 4 days at roomtemperature the solution was concentrated in vacuo to give a solid whichwas chromatographed on silica gel eluting with 3% EtOH/CH₂ Cl₂ to givethe title compound (13.71 g, 61%) as a colorless powder: Anal calcd forC₁₃ H₁₄ N₂ O₄ : C, 59.53; H, 5.40; N, 10.68. Found: C, 59.48; H, 5.47;N, 10.64. MS calcd for C₁₃ H₁₄ N₂ O₄ 262, found 262. DSC=153.2°-155.4°C. at 91.1 J/g.

Example M Preparation of 1,1-Dimethylethyl4-(hydroxyimino)-5-oxo-1-pentyl-3-pyrrolidine carboxylate

To a mechanically stirred solution of the title compound of Example F(17.5 g, 0.065 mol) in 60 ml of pyridine was added hydroxylaminehydrochloride (5.41 g, 0.078 mol) and resulting solution was stirred for36 h. Evaporation of the solvent afforded a light yellow oil which waschromatographed on silica gel eluting with 3% EtOH/CH₂ Cl₂ to give thetitle compound (16.48 g, 89%) as a white solid: Anal calcd for C₁₄ H₂₄N₂ O₄ : C, 59.14, H, 8.51; N, 9.85. Found C, 58.91; H, 8.48; N, 9.71. MScalcd for C₁₄ H₂₄ N₂ O₄ 284, found 284. DSC=131.0°-134.7° C. at 93.1J/g.

Example N Preparation of 1,1-Dimethylethyl4-(hydroxyimino)-5-oxo-1-phenyl-3-pyrrolidine carboxylate

To a solution of the title compound of Example G (9.2 g, 0.033 mol) inpyridine (100 ml) was added hydroxylamine hydrochloride (11.62 g, 0.167mol) and the resulting solution was stirred at room temperature for 4days. Concentration in vacuo gave a solid which was purified on a WatersPrep 500A eluting with 5/95 EtOH/CH₂ Cl₂ to afford the title compound(3.08 g, 32%) as a solid. DSC=187.8°-190.8° C. at 378.5 J/g.

Example O Preparation of 1,1-Dimethylethyl1-(2-fluorophenyl)-4-(hydroxyimino)-5-oxo-3-pyrrolidinecarboxylate

To a solution of the title compound of Example H (3.16 g, 10.8 mmol) inpyridine (50 ml) was added hydroxylamine hydrochloride (3.73 g, 54 mmol)and the reaction was stirred for 5 days(d) at room temperature. Afterthe reaction was concentrated in vacuo, H₂ O was added and the mixturewas extracted with CH₂ Cl₂. Drying of the organic phase (MgSO₄) andconcentration gave a solid which was chromatographed on silica geleluting with 2% EtOH/CH₂ Cl₂ to give the title compound (1.91 g, 57%).Anal calcd for C₁₅ H₁₇ N₂ O₄ F: C, 58.44; H, 5.56; N, 9.09. Found: C,58.43; H, 5.62; N, 8.75. DSC=175.1°-180.2° C. at 225.6 J/g.

Example P Preparation of 1,1-Dimethylethyl4-(hydroxyimino)-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate

To a solution of the title compound of Example I (8.07 g, 27.9 mmol) in150 ml of pyridine was added hydroxylamine hydrochloride (9.69 g, 139mmol) and resulting solution was stirred for 4 d. Addition of H₂ Oresulted in the formation of precipitate which was filtered to give thetitle compound (7.11 g, 84%) as a colorless solid. Calculated for C₁₆H₂₀ N₂ O₄ 1/2H₂ O: C, 61.35; H, 6.76; N, 8.94. Found C, 61.35; H, 6.57,N, 9.34.

Example Q Preparation of Ethyl4-(hydroxyimino)-2-methyl-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To the title compound of Example J (21.6 g, 0.085 mol) in pyridine (150ml) was added hydroxylamine hydrochloride (10.6 g, 0.17 mol) and thesolution was stirred for 5 days. The solvent was removed in vacuo togive an orange oil which was chromatographed on silica gel eluting with2% EtOH/CH₂ Cl₂ to give the title compound (13.67 g, 59%) as an oil.Calculated C₁₃ H₂₂ N₂ O₄ 1/2H₂ O: C, 55.90; H, 8.30; N, 10.02. Found: C,55.99; M, 8.38; N, 10.00. MS calcd for C₁₃ H₂₂ N₂ O₄ 270, found 270.

Example R Preparation of Ethyl4-amino-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

A solution of the title compound of Example K (1.0 g, 3.9 mmol) in 50 mlEtOH w s hydrogenated with 10% palladium on carbon at 60 psi at 60° C.for 18 h. Filtration and evaporation of the solvent gave an oil whichwas chromatographed on silica gel eluting with EtOH/CH₂ Cl₂ (5/95) togive the title compound (382 mg, 40%) as a colorless solid. ¹ H NMR (300MHz, CDCl₃) δ4.20 (2H, q), 3.80 (1H, d), 3.59 (1H, td), 3.48 (1H, q),3.35 (1H, m), 3.29 (2H, m), 1.69 (2H, br s), 1.52 (2H, m), 1.32 (4H, m),1.30 (3H, t), 0.90 (3H, t).

Example S Preparation of Ethyl4-amino-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

A solution of oxime of Example L (791 mg, 3.01 mmol) in 50 ml of EtOHwas hydrogenated with Raney nickel in a 150 ml Parr bomb with 1,000 psiof hydrogen at 50° C. for 4h. The solution was then filtered to removethe catalyst and the solution was concentrated in vacuo. The resultingoil was radially chromatographed on silica gel eluting with 7% EtOH/CH₂Cl₂ to give the title compound (342 mg, 44%). DSC=190.3°-193.8° C. at71.1 J/g.

Example T Preparation of 1,1-Dimethylethyl4-amino-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

A solution of oxime of Example M (20.0 g, 68.6 mmol) in 200 ml of EtOHwas hydrogenated with 10% palladium on carbon at 1200 psi at 70° C. for24 h. Filtration and evaporation of the solution gave the title compound(18.5 g, 100%) as colorless, low-melting solid. MS calcd for C₁₄ H₂₆ N₂O₃ 270, found 270. 'H NMR (300 MH_(z), CDCl₃) δ3.63 (1H, d), 3.50 (1H,m), 3.41 (1H, m), 3.25 (2H, m), 1.72 (2H, s), 1.52 (1H, m), 1.47 (9H,s), 1.29 (4H, m), 0.89 (2H, t).

Example V Preparation of 1,1-Dimethylethyl4-amino-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

A solution of oxime of Example N (3.08 g, 10.6 mmol) in EtOH (B0 ml) washydrogenated at 1000 psi at 70° C. on 10% palladium on carbon.Filtration and concentration of the filtrate gave an oil which waschromatographed on silica gel eluting with 2/97.75/0.25 EtOH/CH₂ Cl₂/NH₄ OH to afford the title compound (1.76 g, 60%) as a white solid.Anal calcd for C₁₅ H₂₀ N₂ O₃ : C, 65.20; H, 7.30; N, 10.14. Found: C,64.95; H, 7.39; N, 10.04. MS calcd for C₁₅ H₂₀ N₂ O₃ 276, found 276.DSC=105.0°-121.1° at 57.2 J/g.

Example W Preparation of 1,1-Dimethylethyl4-amino-1-(2-fluorophenyl)-5-oxo-3-pyrrolidinecarboxylate

A solution of oxime of Example O (1.23 g, 3.99 mmol) in EtOH washydrogenated at 1000 psi on Pd/C at 70° C. for 24 h. The solvent wasremoved in vacuo to give an oil which was chromatographed on silica geleluting with 2% EtOH/CH₂ Cl₂ to give the title compound (850 mg, 72%) asa solid. Anal calcd for C₁₅ H₁₉ N₂ O₃ F: C, 61.21; H, 6.51; N, 9.52; F,6.45. Found: C, 60.87; H, 6.61; N, 9.32; F, 6.10. MS calcd for C₁₅ H₁₉N₂ O₃ F 294, found 294. DSC=71.2°-74.9° C. at 76.6 J/g.

Example X Preparation of 1,1-Dimethylethyl4-amino-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate

A solution of 2.014 g (6.6 mmol) of the oxime of Example P in EtOH (400ml) was hydrogenated with 4% palladium on carbon at 1000 psi at 70° C.for 24 h. Filtration and evaporation of the filtrate gave a white solidwhich was chromatographed on silica gel eluting with 3% CH₃ OH/CH₂ Cl₂/1% NH₄ OH to give the title compound (997 mg, 52%). Anal. calcd. forC₁₆ H₂₂ N₂ O₃ 1/2H₂ O: C, 64.19; H, 7.74; N, 9.36 Found: C, 64.36; H,7.71; N, 9.41.

Example Y Preparation of Ethyl4-amino-2-methyl-5-oxo-1-pentyl-3-pyrroidinecarboxylate

A solution of oxime of Example Q in EtOH is hydrogenated with 10%palladium on carbon at 1200 psi at 70° C. for 24 h. Filtration andevaporation of the filtrate gives a residue which is chromatographed onsilica gel eluting with 2% EtOH/CH₂ Cl₂ to give the title compound.

                  TABLE A                                                         ______________________________________                                        Examples 1 to 26 Have The Following Structures                                 ##STR11##                                                                    Ex   R         R.sub.1 R.sub.4                                                                             X     Ar                                         ______________________________________                                        1    n-pentyl  H       Et    bond  3-quinolinyl                               2    phenyl    H       t-Bu  bond  "                                          3    2-F-phenyl                                                                              H       t-Bu  bond  "                                          4    phenyl    H       Et    bond  2-indolyl                                  5    phenyl    H       t-Bu  bond  "                                          6    benzyl    H       t-Bu  bond  "                                          7    n-pentyl  Me      Et    bond  "                                          8    phenyl    H       Et    CH.sub.2                                                                            3-indolyl                                  9    pentyl    H       t-Bu  bond  3,4-dichlorophenyl                         10   pentyl    H       t-Bu  NH    "                                          11   phenyl    H       Et    bond  "                                          12   phenyl    H       Et    NH    "                                          13   phenyl    H       t-Bu  O     "                                          14   benzyl    H       t-Bu  bond  "                                          15   benzyl    H       t-Bu  NH    "                                          16   n-pentyl  H       Et    bond  2-naphthyl                                 17   n-pentyl  H       t-Bu  NH    "                                          18   phenyl    H       Et    bond  "                                          19   phenyl    H       t-Bu  bond  "                                          20   2-F-phenyl                                                                              H       t-Bu  bond  "                                          21   benzyl    H       t-Bu  bond  "                                          22   n-pentyl  H       t-Bu  bond  4-chlorophenyl                             23   phenyl    H       Et    bond  "                                          24   n-pentyl  H       Et    NH    "                                          25   phenyl    H       t-Bu  bond  3-indazolyl                                26   phenyl    H       t-Bu  bond  2-pyrazinyl                                ______________________________________                                    

EXAMPLE 1 Preparation of Ethylcis-5-oxo-1-pentyl-4-[(3-quinolinylcarbonyl)amino]-3-pyrrolidinecarboxylat

To quinoline-3-carboxylic acid (100 mg, 0.578 mmol) suspended in CH₂ Cl₂was added 2 drops of dimethylformamide followed by the dropwise additionof oxalyl chloride (0.1 ml, 1.15 mmol). After stirring for 2 h at roomtemperature the solution was evaporated to dryness to give the acidchloride. The acid chloride was then redissolved in CH₂ Cl₂ and syringeddropwise into a solution of the aminopyrrolidinone of Example R (140 mg,0.578 mmol) with triethylamine (0.4 ml, 2.89 mmol) in CH₂ Cl₂. Afterstirring for 12 h at room temperature the reaction mixture wasevaporated in vacuo to give an oil which was chromatographed on silicagel eluting with EtOH/CH₂ Cl₂ (2%-5%) to give the title compound (173mg, 75%) as a colorless solid. MS calcd for C₂₂ H₂₇ N₃ O₄ 397, found397.

EXAMPLE 2 Preparation of 1,1-Dimethylethylcis-5-oxo-1-phenyl-4-[(3-quinolinylcarbonyl)amino]-3-pyrrolidinecarboxylate

To a solution of 3-quinolinecarboxylic acid (118 mg, 0.68 mmol) in CH₂Cl₂ (3 ml) was added oxalyl chloride (0.12 ml, 1.36 mmol) and theresulting solution was stirred for 2.5 h at room temperature. Thesolvent was removed in vacuo and the acid chloride was redissolved inCH₂ Cl₂ (3 ml) to which was added the aminopyrrolidinone of Example V(200 mg, 0.68 mmol) and triethylamine (344 mg, 3.4 mmol) in CH₂ Cl₂ (3ml). After stirring for 18 h at room temperature, the solvent wasremoved in vacuo and the resulting oil was purified by radialchromatography on a silica gel plate eluting with 2% EtOH/CH₂ Cl₂ togive the title compound (223 mg, 73%) as a solid. ¹ H NMR (300 MHz,CDCl₃) δ9.38 (1H, d), 8.68 (1H, d), 8.18 (1H, d), 7.94 (1H, d), 7.85(1H, t), 7.64 (2H, d), 7.58 (1H, m), 7.42 (2H, t), 7.21 (1H, t),5.23(1H, t), 4.15 (1H, m), 4.06 (1H, d), 3.81 (1H, t), 1.38 (9H, s).

EXAMPLE 3 Preparation of 1,1-Dimethylethylcis-1-(2-fluorophenyl)-5-oxo-4-[(3-quinolinylcarbonyl)amino]-3-pyrrolidinecarboxylate

To a solution of 3-quinolinecarboxylic acid (118 mg, 0.68 mmol) in CH₂Cl₂ (3 ml) was added oxalyl chloride (0.12 ml, 1.36 mmol) and thesolution was stirred for 2.5 h. Removal of the solvent in vacuo gave acolorless solid which was redissolved in CH₂ Cl₂ (3 ml). To thissolution was added a solution of aminopyrrolidinone of Example W (200mg, 0.68 mmol) and triethylamine (344 mg, 3.4 mmol) in CH₂ Cl₂ (3 ml)and the resulting solution was stirred for 18 h. Removal of the solventin vacuo and purification of the resulting solid via radialchromatography (4 mm plate) eluting with 2% EtOH/CH₂ Cl₂ gave the titlecompound (223 mg, 73%) as a solid. ¹ H NMR (300 MHz, CDCl₃) δ9.35 (1H,d), 8.68 (1H, d), 8.19 (1H, d), 7.94 (1H, d), 7.84 (1H t), 7.64 (1H, t),7.54 (1H, t), 7.32 (1H, m), 7.19 (2H, m), 5.28 (1H, t), 4.21 (1H, m),3.91 (1H, d), 3.78 (1H, q), 3.49 (1H, s), 1.41 (9H, s).

EXAMPLE 4 Preparation of Ethylcis-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To indole-2-carboxylic acid (65 mg, 0.4 mmol) suspended in CH₂ Cl₂ wasadded 2 drops of dimethylformamide followed by the dropwise addition ofoxalyl chloride (0.07 ml, 0.8 mmol). After stirring for 2 h at roomtemperature the solution was evaporated to dryness to give the acidchloride. The acid chloride was then redissolved in CH₂ Cl₂ and syringeddropwise into a solution of the aminopyrrolidinone of Example S (100 mg,0.4 mmol) with triethylamine (0.3 ml, 2.0 mmol) in CH₂ Cl₂. Afterstirring for 12 h at room temperature the reaction mixture wasevaporated in vacuo to give an oil which was chromatographed on silicagel eluting with EtOH/CH₂ Cl₂ 2%-5%) to give the title compound (68 mg,43%) as a colorless solid. ¹ NMR (300 MHz, CDCl₃) δ9.09 (1H, br s), 7.66(4H, m), 7.43 (4 H, t), 7.16 (1H, m), 6.99 (2H, m), 5.21 (1H, t), 4.14(4H, m), 4.05 (1H, m), 3.85 (1H, t), 1.14 (3H, t).

EXAMPLE 5 Preparation of 1,1-Dimethylethylcis-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a solution of indole-2-carboxylic acid (103 mg, 0.64 mmol) in dry DMF(1.5 ml) was added 1,1-carbonyldiimidazole (104 mg, 0.64 mmol) and theresulting solution was stirred for 2.5 h at room temperature. To thismixture was then added a solution of aminopyrrolidinone of Example V(177 mg, 0.64 mmol) in dry DMF (1.5 ml). This solution was then stirredfor 18 h at room temperature after which time the solvent was removed invacuo giving an oil. Chromatography of the oil on a silica gelchromatotron plate (2 mm) eluting with 2/98 EtOH/CH₂ Cl₂ gave the titlecompound (110 mg, 49%) as a solid. ¹ NMR (300 MHz, CDCl₃) δ9.17 (1H, s),7.66 (2H, m), 7.43 (2H, t), 7.32 (1H, t), 7.16 (2H, m), 6.98 (2H, m),5.18 (1 H, q), 4.42 (1H, m), 4.10 (2H, m), 3.76 (1H, t), 1.36 (9H, s).

EXAMPLE 6 Preparation of 1,1-Dimethylethylcis-4-[(1H-indol-2-ylcarbonyl)amino]-5-oxo-1-phenylmethyl)-3-pyrrolidinecarboxylate

To a solution of indole-2-carboxylic acid (183 mg, 1.1 mmol) in DMF wasadded 1,1-carbonyldiimidazole (84 mg, 1.1 mmol). After stirring for 5 hat room temperature a solution of the aminopyrrolidinone of Example X(330 mg 1.1 mmol) in DMF was added. After stirring for 12 h at roomtemperature the reaction mixture was evaporated in vacuo to give an oilwhich was chromatographed on silica gel eluting with EtOH/CH₂ Cl₂(2%-5%) to give 350 mg (73%) of the title compound.

MS calcd for C₃₅ H₂₇ N₃ O₄ 433, found 433.

DSC=206.10°-211.61° C. at 90.50 J/g 217.23° C. at 63.56 J/g.

EXAMPLE 7 Preparation of Ethylcis-4-[(1H-indol-2-ylcarbonyl)amino]-2-methyl-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To indole-2-carboxylic acid (0.264 mg, 1.6 mmol) in DMF (3 ml.) wasadded 1,1-carbonyldiimidazole (260 mg, 1.6 mmol). After stirring for 4 hat room temperature a solution of the aminopyrrolidinone of Example Y(408 mg, 1.6 mmol) in DMF was added. After stirring for 24 h at roomtemperature the reaction mixture was evaporated in vacuo to give an oilwhich was chromatographed on silica gel eluting with EtOH/CH₂ Cl₂(2%-5%) to give the title compound, 600 mg (95%). ¹ NMR (300 MHz, CDCl₃)δ0.98 (t, 3H), 3.75 (m, 1H), 3.96 (m, 1H), 4.02 (m, 2H), 4.19 (m, 1H),5.15 (t, 1H), 7.04 (t, 1H), 7.27 (m, 2H), 7.43 (t, 2H), 7.61 (d, 1H),7.72 (d, 1H), 8.99 (d, 1H).

EXAMPLE 8 Preparation of Ethylcis-4-[(1H-indol-3-ylacetyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a solution of indole-3-acetic acid (248 mg, 1.42 mmol) in DMF (3 ml)was added 1,1-carbonyldiimidazole (230 mg, 1.42 mmol). After stirringfor 2 h a solution of the aminopyrrolidinone of Example S (352 mg, 1.42mmol) in DMF (1 ml) was added. After stirring for an additional 18 h thesolvent was evaporated to give an oil which was chromatographed onsilica gel eluting with EtOH/CH₂ Cl₂ (2%-5%) to give 470 mg (91%) of thetitle compound as a solid. NMR (DMSO) 400 MH_(z) : 3.25δ, m, 1H; 3.59δ,d, 2H; 3.88δ, t, 1H; 4.01δ, t, 1H; 4.65δ, q, 1H; 6.98δ, t, 1H; 7.08δ, t,1H; 7.15δ, t, 1H; 7.24δ, d, 1H; 7.37, m, 3H; 7.56δ, d, 1H; 7.78δ, d, 2H;8.62δ, d, 1H.

EXAMPLE 9 Preparation of 1,1-Dimethylethylcis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To a solution of the aminopyrrolidinone of Example T (110 mg, 0.407mmol) and triethylamine (0.11 ml, 0.814 mmol) in CH₂ Cl₂ was added asolution of 3,4-dichlorobenzoyl chloride (85 mg, 0.407 mmol) in CH₂ Cl₂dropwise via syringe. After stirring for 12 h at room temperature thereaction mixture was evaporated in vacuo to give an oil which waschromatographed on silica gel eluting with EtOH/CH₂ Cl₂ (2%-5%) to givethe title compound (150 mg, 85%) as a colorless solid. DSC=108.1-111.3at 38.5 J/g. Anal calcd for C₂₁ H₂₈ N₂ O₄ Cl₂ : C, 56.89; H, 6.36; N,6.32. Found C, 57.09; H, 5.87; N, 6.22. MS calcd for C₂₁ H₂₈ N₂ O₄ Cl₂443, found 443.

EXAMPLE 10 Preparation of 1,1-Dimethylethylcis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To a solution of 3,4-dichlorophenyl isocyanate (76 mg, 0.407 mmol)dissolved in 3 ml of CH₂ Cl₂ was added a solution of aminopyrrolidinoneof Example T (110 mg, 0.407 mmol) in 3 ml of CH₂ Cl₂ and the resultingsolution was stirred for 16 h at room temperature. Evaporation of thesolvent in vacuo gave a solid which was purified on silica gel elutingwith 5/95 EtOH/CH₂ Cl₂ to give the title compound (167 mg, 90%) as acolorless solid. DSC=162.0°-164.2° C. at 65.0 J/g. MS calculated for C₂₁H₂₉ N₃ O₄ Cl₂ 458, found 458.

EXAMPLE 11 Preparation of Ethylcis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a solution of 3,4-dichlorobenzoyl chloride (295 mg, 1.41 mmol) in CH₂Cl₂ (4 ml) was added a solution of aminopyrrolidinone of Example S (350mg, 1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH₂ Cl₂ (4 ml)and the resulting solution was stirred for 18 h at room temperature.Concentration in vacuo gave an oil which was chromatographed on silicagel eluting with 2% EtOH/CH₂ Cl₂ to give the title compound (400 mg,67%) as a colorless solid. Anal calcd for C₂₀ H₁₈ N₂ O₄ Cl₂ : C, 57.02;H, 4.31; N, 6.65. Found: C, 57.05; H, 4.39; N, 6.50. MS M+1 calcd forC₂₀ H₁₈ N₂ O₄ Cl₂ 422, found 422. DSC=185.5°-193.1° C. at 82.8 J/g.

EXAMPLE 12 Preparation of Ethylcis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a solution of 3,4-dichlorophenylisocyanate in CH₂ Cl₂ (3 ml) wasadded a solution of aminopyrrolidinone of Example S (350 mg, 1.41 mmol)in CH₂ Cl₂ (3 ml) and the resulting solution was stirred for 18 h atroom temperature. Concentration in vacuo gave a solid which wastriturated with CH₂ Cl₂ and filtered to give the title compound (420 mg,68%) as a solid. MS M+1 calcd for C₂₀ H₁₉ N₃ O₄ Cl₂ 437, found 437DSC=249.1°-251.7° C. at 112.7 J/g.

EXAMPLE 13 Preparation of 1,1-Dimethylethylcis-4-[[(3,4-dichlorophenoxy)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a cooled (0° C.) solution of aminopyrrolidinone of Example V (300 mg,1.09 mmol) and triethylamine (0.15 mL, 1.09 mmol) in CH₂ Cl₂ is added3,4-dichlorophenyl chloroformate (207 mg, 1.09 mmol). After warming toroom temperature the reaction is stirred for 12 h. The reaction mixtureis then washed with water and brine, dried (MgSO₄) and concentrated invacuo to give a residue which is chromatographed on silica gel elutingwith EtOH/CH₂ Cl₂ (2%-5%) to give the title compound.

EXAMPLE 14 Preparation of 1,1,-Dimethylethylcis-4-[[(3,4dichlorophenyl)carbonyl]amino]-5-oxo-1-phenylmethyl-3-pyrrolidinecarboxylate

To a solution of 3,4 dichlorobenzoyl chloride (419 mg, 2.0 mmol) in CH₂Cl₂ (3 ml) was added a solution of aminopyrrolidinone of Example X (286mg, 0.99 mmol) and triethylamine (0.28 ml, 2.0 mmol) in CH₂ Cl₂ (3 ml).After stirring for 18 h at room temperature the reaction mixture wasevaporated in vacuo to give a solid which was chromatographed on silicagel eluting with 2% EtOH/CH₂ Cl₂ to give 352 mg (77%) of the titlecompound.

Anal calcd for C₂₃ H₂₄ N₂ O₄ Cl₂ : C, 59.62; H, 5.22; N, 6.05. Found C,59.20; H, 5.31; N, 5.90. DSC=132.64°-140.52° C. at 50.30 J/g.

EXAMPLE 15 Preparation of 1,1-dimethylethylcis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate

To a solution of 3,4-dichlorophenyl isocyanate (194 mg, 1.0 mmol) in CH₂Cl₂ (3 ml) was added aminopyrrolidinone of Example X (300 mg, 1.0 mmol)in CH₂ Cl₂ (2 ml). After stirring for 48 h the solvent was concentratedin vacuo to give a solid which was chromatographed on silica gel elutingwith 5% EtOH/CH₂ Cl₂ to give 425 mg (89%) of the title compound.

Anal Calcd for C₂₃ H₂₅ N₃ O₄ Cl₂ : C, 57.75; H, 5.27; N, 8.78; Cl,14.82. Found C, 57.93; H, 5.38; N, 8.65; Cl, 14.97. DSC=188.62°C.-190.68° C. at 78.73 J/g.

MS calcd for C₂₃ H₂₅ N₃ O₄ Cl₂ 478, found 478.

EXAMPLE 16 Preparation of Ethylcis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To a solution of the aminopyrrolidinone of Example R (120 mg, 0.495mmol) and triethylamine (0.35 ml, 2.48 mmol) in CH₂ Cl₂ was added asolution of 2-naphthoyl chloride (94 mg, 0.495 mmol) in CH₂ Cl₂ dropwisevia syringe. After stirring for 12 h at room temperature the reactionmixture was evaporated in vacuo to give a residue which waschromatographed on silica gel eluting with EtOH/CH₂ Cl₂ (2%-5%) to givethe title compound (172 mg, 69%) as a colorless solid. MS M+1 calcd forC₂₃ H₂₈ N₂ O₄ 397; found 397.

EXAMPLE 17 Preparation of 1,1-Dimethylethylcis-4-[[(2-naphthalenylamino)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To a solution of 2-naphthyl isocyanate (69 mg, 0.407 mmol) dissolved in3 ml of CH₂ Cl₂ was added a solution of the amine of Example T (110 mg,0.407 mmol) in 3 ml of CH₂ Cl₂ and the resulting solution was stirredfor 16 h at room temperature. Evaporation of the solvent in vacuo gave asolid which was purified on silica gel eluting with 5/95 EtOH/CH₂ Cl₂ togive the title compound (130 mg, 73%) as a colorless solid. MS calcd forC₂₅ H₃₃ N₃ O₄ 439, found 439.

EXAMPLE 18 Preparation of Ethylcis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a solution of the aminopyrrolidinone of Example S (1.54 g, 6.2 mmol)and triethylamine (1.3 ml, 9.3 mmol) in CH₂ Cl₂ (10 ml) was added asolution of 2-naphthoyl chloride (1.18 g, 6.2 mmol) in CH₂ Cl₂ (7 ml)dropwise via syringe. After stirring for 12 h at room temperature thereaction mixture was evaporated in vacuo to give a residue which waschromatographed on silica gel eluting with EtOH/CH₂ Cl₂ (2%-5%) to givethe title compound (2.5 g, 100%) as a colorless solid. Anal calcd forC₂₄ H₂₂ N₂ O₄ : C, 71.63; H, 5.51; N, 6.96. Found C, 71.31; H, 5.45; N,6.73. MS calcd for C₂₄ H₂₂ N₂ O₄ 402; found 402.

EXAMPLE 19 Preparation of 1,1-Dimethylethylcis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a solution of 2-naphthoyl chloride (1.20 g, 6.29 mmol) in CH₂ Cl₂ (9ml) was added a solution of aminopyrrolidinone of Example V (1.56 g,5.64 mmol) and triethylamine (1.31 ml, 9.43 mmol) in CH₂ Cl₂ (10 ml) andthe resulting solution was stirred for 60 h at room temperature. Afterremoving the solvent in vacuo, H₂ O was added and the mixture wasextracted with CH₂ Cl₂. The combined organic layers were washed withbrine, dried (MgSO₄), filtered and concentrated under reduced pressureto give a solid which was chromatographed on silica gel eluting with 2%EtOH/CH₂ Cl₂ to give the title compound (2.28 g, 94%) as a colorlesssolid. Anal calcd for C₂₆ H₂₆ N₂ O₄.2/3H₂ O: C, 70.57; H, 5.92; N, 6.33.Found: C, 70.36; H, 6.16; N, 6.23. MS calcd for C₂₆ H.sub. 26 N₂ O₄ 430,found 430. DSC=182.4°-185.1° C. at 107.4 J/g.

EXAMPLE 20 Preparation of 1,1-Dimethylethylcis-1-(2-fluorophenyl)-4-[(2naphthalenylcarbonyl)amino]-5-oxo-3-pyrrolidinecarboxylate

To a solution of 2-naphthoyl chloride (178 mg, 0.934 mmol) in CH₂ Cl₂ (3ml) was added a solution of aminopyrrolidinone of Example W (250 mg,0.849 mmol) and triethylamine (146 mg, 1.44 mmol) in CH₂ Cl₂ (3 ml) andthe resulting solution was stirred at room temperature for 18 h. Thesolvent was then removed in vacuo and the resulting foam was purified byradial chromatography on a silica gel plate (4 mm) eluting with 2/98EtOH/CH₂ Cl₂ to give the title compound (380 mg, 100%) as a colorlessfoam. MS M+1 calcd for C₂₆ H₂₅ N₂ O₄ F 449, found 449. DSC=142.2°-151.5°C.@55.9 J/g.

EXAMPLE 21 Preparation of 1,1-dimethylethylcis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylate

To a solution of 2-naphthoyl chloride (210 mg, 1.1 mmol) in CH₂ Cl₂ (3ml) was added a solution of aminopyrrolidinone of Example X (300 mg, 1.0mmol) and triethylamine (0.24 ml, 1.7 mmol) in CH₂ Cl₂ (3 ml). Afterstirring for 18 h at room temperature the reaction mixture wasevaporated in vacuo to give an oil which was purified by radialchromatography on silica gel eluting with EtOH/CH₂ Cl₂ (2%) to give thetitle compound 363 mg (82%).

DSC=124.38°-128.68° C.@49.93 (99.73) J/g.

EXAMPLE 22 Preparation of 1,1-Dimethylethylcis-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To a solution of the aminopyrrolidinone of Example T (116 mg, 0.429mmol) and triethylamine (0.12 ml, 0.858 mmol) in CH₂ Cl₂ was added asolution of 4-chlorobenzoyl chloride (75 mg, 0.429 mmol) in CH₂ Cl₂dropwise via syringe. After stirring for 12 h at room temperature thereaction mixture was evaporated in vacuo to give a residue which waschromatographed on silica gel eluting with EtOH/CH₂ Cl₂ (2%-5%) to givethe title compound (160 mg, 91%) as a colorless solid. DSC=100.4°-105.1°C. at 52.7 J/g. Anal calcd for C₂₁ H₂₉ N₂ O₄ Cl: C, 61.68; H, 7.15; N,6.85. Found C, 61.20; H, 7.06; N, 6.58. MS calcd for C₂₁ H₂₉ N₂ O₄ Cl409, found 409.

EXAMPLE 23 Preparation of Ethylcis-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To a solution of p-chlorobenzoyl chloride (247 mg, 1.41 mmol) in CH₂ Cl₂(4 ml) was added a solution of aminopyrrolidinone of Example S (350 mg,1.41 mmol) and triethylamine (0.4 ml, 2.82 mmol) in CH₂ Cl₂ (4 ml) andthe resulting solution was stirred for 18 h at room temperature.Concentration in vacuo gave an oil which was chromatographed on silicagel eluting with 5/95 EtOH/CH₂ Cl₂ to give the title compound (378 mg,68%) as a solid. Anal calcd for C₂₀ H₁₉ N₂ O₄ Cl: C, 62.10; H, 4.95; N,7.24. Found: C, 62.07; H, 5.05; N, 7.18. MS calcd for C₂₀ H₁₉ N₂ O₄ Cl386, found 386. DSC=215.2°-216.8° C. at 144.3 J/g.

EXAMPLE 24 Preparation of ethylcis-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylate

To a solution of 4-chlorophenyl isocyanate (113 mg, 0.734 mmol) in CH₂Cl₂ (1 ml) was added the aminopyrrolidinone of Example R (178 mg, 0.734mmol) in CH₂ Cl₂ (1ml). After stirring for 18 h, the solvent was removedin vacuo and the resulting mixture was chromatographed on silica gel (5%EtOH/CH₂ Cl₂) to give the title compound (210 mg, 72%). 'H NMR (300MH_(z), CDCl₃) δ7.99 (1H, s), 7.42 (2H, d), 7.24 (2H, t), 6.21 (1H, d),4.92 (1H, q), 4.21 (1H, m), 4.11 (1H, m), 3.55 (2H, q), 3 32 (2H, m),1.55 (2H, q), 1.29 (4H, m), 1.21 (2H, t), 0.89 (3H, t).

EXAMPLE 25 Preparation of 1,1-Dimethylethylcis-4-[(1H-indazol-3-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate

To indazole-3-carboxylic acid (176 mg, 1.08 mmol) [prepared according tothe procedure in J. Am Chem. Soc. 74. 2009 (1952)] in DMF (2 ml) wasadded 1,1-carbonyldiimidazole (176 mg, 1.08 mmol). After stirring for 4h at room temperature a solution of the aminopyrrolidinone of Example V(300 mg, 1.08 mmol) in DMF was added. After stirring for 12 h at roomtemperature the reaction mixture was evaporated in vacuo to give 260 mg(57%) of an oil which was chromatographed on silica gel eluting withEtOH/CH₂ Cl₂ (2%-5%) to give the title compound.

Anal calcd for C₂₃ H₂₄ N₄ O₄ : C, 65.70; H, 5.75; N, 13.32. Found C,65.73; H, 5.90; N, 13.12. DSC=200.48° C.-205.71° C. at 168.55 J/g.

EXAMPLE 26 Preparation of 1,1-Dimethylethylcis-5-oxo-1-phenyl-4-[(2-pyrazinylcarbonyl)amino]-3-pyrrolidinecarboxylate

To 2-pyrazinecarboxylic acid (90 mg, 0.72 mmol) in DMF (2 ml) was added1,1-carbonyldiimidazole (117 mg, 0.72 mmol). After stirring for 4 h atroom temperature a solution of the aminopyrrolidinone of Example V (200mg, 0.72 mmol) in DMF was added. After stirring for 18 h at roomtemperature the reaction mixture was evaporated in vacuo to give an oilwhich was chromatographed on silica gel eluting with EtOH/CH₂ Cl₂(2%-5%) to give the title compound, 140 mg (51%). MS calcd for C₂₀ H₂₂N₄ O₄ 382, found 382.

EXAMPLE 27 Preparation of ##STR12##

To the ethyl ester of Example 1 (173 mg, 0.435 mmol) dissolved in 4:1EtOH/THF was added an aqueous solution of lithium hydroxide (31 mg, 1.29mmol). After stirring for 16 h at room temperature 2.5 ml of water wasadded and the solution was extracted with chloroform. The aqueous layerwas then acidified with 1N HCl to pH=2 and extracted again withchloroform. The combined organic layers were dried over MgO₄, filteredand concentrated in vacuo to give the crude acid which waschromatographed on silica gel eluting with 5/95/1 EtOH/CH₂ Cl₂ /HOAc togive the title compound (31 mg, 19%) as a colorless powder. MS M+1 calcdfor C₂₀ H₂₃ N₃ O₄ 370; found 370.

EXAMPLE 28 Preparation of ##STR13##

The tert-butyl ester of Example 3 (223 mg, 0.496 mmol) was dissolved intrifluoroacetic acid (11 ml) and stirred for 8 h at room temperature.Concentration in vacuo gave a yellow oil which was purified by radialchromatography on a silica gel plate (2 mm) eluting with 10/89/1EtOH/CH₂ Cl₂ /HOAc to give the title compound (178 mg, 63%). MS calcdfor C₂₁ H₁₆ N₃ O₄ F 393, found 393. DSC=293.2°-297.4° C.@147.7 J/g.

EXAMPLE 29 Preparation of ##STR14##

The tert-butyl ester of Example 5 (110 mg, 0.26 mmol) was dissolved in 3ml of trifluoroacetic acid and the resulting solution was stirred for 2days at room temperature. Concentration in vacuo gave an oil which waschromatographed on silica gel eluting with 5/91/1 EtOH/CH₂ Cl₂ /HOAc togive the title compound (41 mg, 43%) as a colorless solid. MS calcd forC₂₀ H₁₇ N₃ O₄ 363, found 363. DSC=214.2°-229.3° C.@48.7 J/g.

EXAMPLE 30 Preparation of ##STR15##

To the ethyl ester of Example 4 (68 mg, 0.174 mmol) dissolved in 4:1EtOH/THF was added an aqueous solution of lithium hydroxide (13 mg,0.521 mmol). After stirring for 16 h at room temperature, 2.5 ml ofwater was added and the solution was extracted with chloroform. Theaqueous layer was then acidified with 1N HCl to pH2 and extracted againwith chloroform. The combined organic layers were dried over MgO₄,filtered and concentrated in vacuo to give the crude acid which waschromatographed on silica gel eluting with 5/95/1 EtOH/CH₂ Cl₂ /HOAc togive the title compound (27 mg, 42%) as a colorless powder. Anal calcdfor C₂₀ H₁₇ N₃ O₄ : C, 64.51; H, 4.87; N, 11.28. Found: C, 64.26; H,4.62; N, 10.88. MS M+1 calcd for C₂₀ H₁₇ N₃ O₄ 364, found 364.

EXAMPLE 31 Preparation of ##STR16##

The tert-butyl ester 320 mg (0.738 mmol) of Example 6 was dissolved intrifluoroacetic acid (2 ml) and stirred for 3.5 h at room temperatureafter which time the reaction was concentrated in vacuo. The resultingmaterial was recrystallized from CH₂ Cl₂, to give 94 mg (34%) of thetitle compound. Anal calcd for C₂₁ H₁₉ N₃ O₄.1/4H₂ O.C,66.04; H,5.15;N,11.00. Found C,66.21; H,5.34; N,10.62. MS calcd 377, found 377.DSC=240.75°-246.18° C.@122.6 J/g.

EXAMPLE 32 Preparation of ##STR17##

The tert-butyl ester of Example 9 (145 mg, 0.327 mmol) was dissolved in5 ml of trifluoroacetic acid and stirred for 16 h at room temperatureafter which time the reaction was concentrated in vacuo. The resultingmaterial was radially chromatographed on silica gel eluting withEtOH/CH₂ Cl₂ /HOAc (5/95/1) to give the title compound (89 mg, 77%) as acolorless solid. Anal calcd for C₁₇ H₂₀ N₂ O₄ Cl₂ : C, 52.73; H, 5.20;N, 7.23. Found: C, 52.43; H, 5.32; N, 7.02. DSC=204.6°-210.2° C.@54.8J/g. MS M+1 calcd for C₁₇ H₂₀ N₂ O₄ Cl₂ 387, found 387.

EXAMPLE 33 Preparation of ##STR18##

The tert-butyl ester of Example 14 (301 mg, 0.65 mmol) was dissolved intrifluoroacetic acid (3 ml) and stirred for 3.5 h after which time thereaction was concentrated in vacuo. The residue was resuspended in CH₂Cl₂ and filtered to give 155 mg (58%) of the title compound as a solid.Anal Calcd for C₁₉ H₁₆ N₂ O₄ Cl₂.1/4H₂ O: C,55.42; H,4.04; N,6.80.Found: C.55.43; H,4.13; N,6.83. DSC=217.26°-219.87° C. at 104.8 J/g. MSM+1 calcd for C₁₉ H₁₆ N₂ O₄ Cl₂ 408, found 408.

EXAMPLE 34 Preparation of ##STR19##

The tert-butyl ester of Example 10 (160 mg, 0.35 mmol) was dissolved in5 ml of trifluoroacetic acid and stirred for 16 h at room temperatureafter which time the reaction was concentrated in vacuo. The resultingmaterial was radially chromatographed on silica gel eluting withEtOH/CH₂ Cl₂ /HOAc (5/95/1) to give the title compound (119 mg, 85%) asa colorless solid. DSC=139.0°-143° C.@5.7 J/g and 191.7°- 203.5° C.@99.6J/g. MS M+1 calcd for C₁₇ H₂₁ N₃ O₄ Cl₂ 403, found 403.

EXAMPLE 35 Preparation of ##STR20##

To a solution of ethyl ester of Example 11 (394 mg, 0.935 mmol) inEtOH/THF (10 ml, 4:1 EtOH/THF) was added a solution of lithium hydroxide(33 mg, 1.4 mmol) in 1 ml H₂ O and the resulting solution was stirredfor 2 h at room temperature. Concentration in vacuo gave a solid whichwas chromatographed on silica gel eluting with 2/97/1 EtOH/CH₂ Cl₂ /HOActo give the cis-substituted carboxylic acid Compound A (31 mg, 8.4%) asa colorless solid. Anal calcd for C₁₈ H₁₄ N₂ O₄ Cl₂ : C, 54.97; H, 3.59;N, 7.12. Found: C, 55.10; H, 3.61; N, 6.66. MS M+1 Calcd for C₁₈ H₁₄ N₂O₄ Cl₂ 394, found 394. DSC=220°-227.7° C. at 70.9 J/g. Continued elutiongave the trans-substituted carboxylic acid Compound B (290 mg, 79%) as acolorless solid. Anal calcd for C₁₈ H₁₄ N₂ O₄ Cl₂ : C, 54.97; H, 3.59;N, 7.12. Found: C, 54.70; H, 3.51; N, 6.98. MS M+1 calcd for C₁₈ H₁₄ N₂O₄ Cl₂ 394, found 394. DSC=234.2°-237.0° C.@80.1 J/g.

EXAMPLE 36 Preparation of ##STR21##

To a solution of ethyl ester of Example 12 (420 mg, 0.96 mmol) inEtOH/THF (10 ml of 1:4 EtOH/THF) was added a solution of lithiumhydroxide (35 mg, 1.4 mmol) in H₂ O (3 ml) and the resulting solutionwas stirred for 2 h at room temperature. The reaction mixture was thenacidified to pH=2 with 1N HCl. Removal of the solvent gave a yellowsolid which was chromatographed on silica gel eluting with 2/97/1EtOH/CH₂ Cl₂ /HOAc to give the cis-substituted Compound A (62 mg, 16%)as a colorless solid. MS calcd for C₁₈ H₁₅ N₃ O₄ Cl₂ 408, found 408.DSC=229.1°-238.7° C.@281.6 J/g. Continued elution gave thetrans-substituted Compound B (160 mg, 41%) as a colorless solid: MScalcd for C₁₈ H₁₅ N₃ O₄ Cl₂ 408, found 408. DSC=243.5°-249.7 ° C.@218.2J/g.

EXAMPLE 37 Preparation of ##STR22##

The tert-butyl ester of Example 15 (410 mg, 0.857 mmol) was dissolved intrifluoroacetic acid (3 ml) and stirred for 4 h after which time thereaction was concentrated in vacuo. The residue was resuspended in MeOHand filtered to give the title compound (143 mg, 40%) as a solid. Analcalcd for C₁₉ H₁₇ N₃ O₄ Cl₂.1/4H₂ O: C,53.47; H,4.13; N,9.85. FoundC,53.24; H,4.12; N,9.63. DSC=213.82°-216.88° C.@121.3 J/g.

EXAMPLE 38 Preparation of ##STR23##

The tert-butyl ester of Example 13 is dissolved in trifluoroacetic acidand stirred for 16 h at room temperature after which time the reactionis concentrated in vacuo. The resulting material is purified bychromatography on silica gel eluting with EtOH/CH₂ Cl₂ /HOAc to give thetitle compound.

EXAMPLE 39 Preparation of ##STR24##

To the ethyl ester of Example 16 (170 mg, 0.429 mmol) dissolved in 4:1EtOH/THF was added an aqueous solution of lithium hydroxide (31 mg, 1.29mmol). After stirring for 16 h at room temperature, 2.5 ml of water wasadded and the solution was extracted with chloroform. The aqueous layerwas then acidified with 1N HCl to pH=2 and extracted again withchloroform. The combined organic layers were dried over MgO₄, filteredand concentrated in vacuo to give the crude acid which waschromatographed on silica gel eluting with 5/95/1 EtOH/CH₂ Cl₂ /HOAc togive the title compound (45 mg, 28%) as a colorless powder. Anal calcdfor C₂₁ H₂₆ N₂ O₅.H₂ O: C, 65.27; H, 6.26; N, 7.61. Found C, 65.45; H,6.52; N, 7.11. MS M+1 calcd for C₂₁ H₂₆ N₂ O₅ 369, found 369.

EXAMPLE 40 Preparation of ##STR25##

The tert-butyl ester of Example 17 (130 mg, 0.296 mmol) was dissolved in5 ml of trifluoroacetic acid and stirred for 16 h at room temperatureafter which time the reaction was concentrated in vacuo. The resultingmaterial was chromatographed on silica gel on a chromatotron plateeluting with EtOH/CH₂ Cl₂ /HOAc (5/95/1) to give the title compound (63mg, 55%) as a colorless solid. Anal calcd. for C₂₁ H₂₅ N₃ O₅ : C, 65.78;H, 6.57; N, 10.96. Found: C, 65.31; H, 6.62; N, 10.75. DSC=228.8-231.3at 293.2 J/g. MS calcd for C₂₁ H₂₅ N₃ O₅ 383, found 383.

EXAMPLE 41 Preparation of ##STR26##

To the ethyl ester of Example 18 (1.92 g, 4.8 mmol) dissolved in 4:1EtOH/THF (100 ml) was added a solution of lithium hydroxide (575 mg, 24mmol). After stirring for 2 h at room temperature, 70 ml of water wasadded and the solution was extracted with chloroform. The aqueous layerwas then acidified with 1N HCl to pH=2 and extracted again withchloroform. The combined organic layers were dried over MgO₄, filteredand concentrated in vacuo to give the crude acid which wasrecrystallized from CH₂ Cl₂ to give the trans carboxylic acid Compound B(1.19 g, 66%) as a colorless powder. Anal calcd for C₂₂ H₁₈ N₂ O₄.1/2H₂O: C, 68.92; H, 4.99; N, 7.30. Found: C, 68.57; H, 4.68; N, 7.17. MS M+1calcd for C₂₂ H₁₈ N₂ O₄ 375; found 375. DSC= 250.0-251.9 at 112.3 J/g.Chromatography of the mother liquor on silica gel eluting with 10/89/1EtOH/CH₂ Cl₂ /HOAc gave the higher-Rf, cis isomer Compound A (232 mg,12%) as a colorless powder. Anal calcd for C₂₂ H₁₈ N₂ O₄.1/4H₂ O: C,69.74; H, 4.92; N, 7.39. Found: C, 69.90; H, 4.94; N, 7.19.DSC=211.7°-214.9° C. at 94.5 J/g. MS calcd for C₂₂ H₁₈ N₂ O₄ 374, found374.

EXAMPLE 42 Preparation of ##STR27##

The tert-butyl ester of Example 19 (2.14 g, 7.97 mmol) was dissolved in10 ml of trifluoroacetic acid and stirred for 18 h at room temperatureafter which time the reaction was concentrated in vacuo. The resultingsolid was purified by chromatography on silica gel eluting with MeOH/CH₂Cl₂ /HOAc (3/96/1) to give the title compound (1.56 g, 84%) as acolorless solid Anal calcd for C₂₂ H₁₈ N₂ O₄.1/4H₂ O: C, 69.74; H, 4.92;N, 7.39. Found: C, 69.90; H, 4.86; N, 7.30. MS calcd for C₂₂ H₁₈ N₂ O₄374, found 374. DSC=212.9°-216.0° C. at 100.9 J/g.

EXAMPLE 43 Preparation of ##STR28##

The tert-butyl ester of example 21 (303 mg, 0.7 mmol) was dissolved intrifluoroacetic acid (3 ml) and stirred for 3.5 h after which time thereaction was concentrated in vacuo. Resuspension of the residue in CH₂Cl₂ and filtration gave the title compound (161 mg, 59%) as a solid.Anal calcd for C₂₃ H₂₀ N₂ O₄.1/4H₂ O: C, 70.30; H, 5.26; N,7.13. FoundC,70.52; H,5.44; N,7.10. DSC=213.37°-216.45° C.@107.5 J/g. MS calc forC₂₃ H₂₀ N₂ O₄ 388, found 388.

EXAMPLE 44 Preparation of ##STR29##

The tert-butyl ester of Example 20 (388 mg, 0.865 mmol) was dissolved in3 ml of trifluoroacetic acid and stirred for 18 h at room temperature.Concentration in vacuo gave a solid which was chromatographed on asilica gel chromatotron plate (4 mm) eluting with 3/1/96 EtOH/CH₂ Cl₂/HOAc to give the title compound (183 mg, 54%) as a solid. Anal calcdfor C₂₂ H₁₇ N₂ O₄ F. H₂ O: C, 66.40; H, 4.67; N, 6.83. Found: C, 64.55;H, 4.42; N, 6.71. MS calcd for C₂₂ H₁₇ N₂ O₄ F 392, found 392.DSC=182.9°-185.2° C.@94.1 J/g.

EXAMPLE 45 Preparation of ##STR30##

The tert-butyl ester of Example 22 (160 mg, 0.39 mmol) was dissolved in4 ml of trifluoroacetic acid and stirred for 16 h at room temperatureafter which time the reaction was concentrated in vacuo. The resultingmaterial was chromatographed on silica gel on a chromatotron plateeluting with EtOH/CH₂ Cl₂ /HOAc (5/95/1) to give the title compound (65mg, 41%) as a colorless solid. DSC=193.3°-195.8° C.@71.2 J/g.

MS calcd for C₁₇ H₂₁ N₂ O₄ Cl 352, found 352.

EXAMPLE 46 Preparation of ##STR31##

To a solution of ethyl ester of Example 23 (378 mg, 0.977 mmol) inEtOH/THF (10 ml of 1:4 EtOH THF) was added a solution of lithiumhydroxide (35 mg, 0.147 mmol) in H₂ O (1 ml) and the resulting solutionwas stirred for 2 h at room temperature. Concentration in vacuo gave aresidue which was chromatographed on silica gel eluting with 2/97/1EtOH/CH₂ Cl₂ /HOAc to give the desired cis-substituted Compound A (28mg, 8%) as a colorless solid. MS M+1 calcd for C₁₈ H₁₄ N₂ O₄ Cl 359,found 359. DSC=211.71-220.08@51.42 J/g. Continue elution afforded thetrans-substituted carboxylic acid Compound B (213 mg, 61%) as acolorless solid. Anal calcd for C₁₈ H₁₄ N₂ O₄ Cl.1/2H₂ O: C, 58.79; H,4.38; N, 7.61. Found: C, 58.41; H, 4.35; N, 7.10. MS calcd for C₁₈ H₁₄N₂ O₄ Cl 358, found 358. DSC=216.2°-223.0° C.@84.2 J/g.

EXAMPLE 47 Preparation of ##STR32##

To a solution of the ethyl ester (210 mg, 0.530 mmol) of example 24 in1:4 EtOH/THF (4 ml) was added a solution of lithium hydroxide 13 mg,0.53 mmol) in water (1 ml) and the reaction was stirred at roomtemperature for 2 h. The reaction mixture was acidified with 1N HCl topH=4 and concentrated in vacuo to give a solid which was purified bychromatography on silica gel eluting with MeOH/CH₂ Cl₂ /HOAc (10/89/1)to give the cis isomer (70. mg, 38%): Anal calcd for C₁₇ H₂₂ N₃ O₄ Cl.H₂O: C, 52.92; H, 5.75; N, 10.89. Found: C, 52.97; H, 5.64; N, 10.36. MScalcd for C₁₇ H₂₂ N₃ O₄ Cl 368, found 368. Continued elution gave thetrans isomer (88 mg, 45%).

Anal calcd for C₁₇ H₂₂ N₃ O₄ Cl:H₂ O: C, 52.92; H, 5.75; N, 10.89.Found: 53.17; H, 5.79; N, 10.40. MS calcd for C₁₇ H₂₂ N₃ O₄ Cl 368,found 368.

EXAMPLE 48 Preparation of ##STR33##

The tert-butyl ester (230 mg 0.547 mmol) of Example 25 was dissolved intrifluoroacetic acid (3 ml) and stirred for 20 min at room temperatureafter which time the reaction was concentrated in vacuo. Resuspension ofthe residue in CH₂ Cl₂ and filtration gave the title compound (206 mg,79%) as a colorless solid. Anal calcd for C₁₉ H₁₆ N₄ O₄.8/10CF₃ CO₂ H:C,54.41; H,3.55; N,12.32; F,10.03. Found C,54.52; H,3.76; N,12.45;F,10.35. DSC=130.85°-140.96° C. at 97.64 J/g. MS calc. for C₁₉ H₁₆ N₄ O₄364, found 364.

EXAMPLE 49 Preparation of ##STR34##

The tert-butyl ester (120 mg 0.314 mmol) of Example 26 was dissolved intrifluoroacetic acid 2 ml and stirred for 3.5 h at room temperatureafter which time the reaction was concentrated in vacuo. The resultingmaterial was chromatographed on silica gel eluting with EtOH/CH₂ Cl₂/HOAc (5/95/1) to give 55 mg (54%) of the title compound, MS calcd forC₁₆ H₁₄ N₄ O₄ : 326, found 326.

EXAMPLE 50 Preparation of ##STR35##

To a solution of Example 7 (600 mg, 1.5 mmol) in EtOH/THF (20 ml of 1:4EtOH/THF) was added a solution of lithium hydroxide (55 mg, 2.3 mmol) inH₂ O (10 ml) and the resulting solution was stirred for 2 h at roomtemperature. The reaction mixture was then acidified to pH 2 with 1NHCl. Removal of the solvent gave the title compound.

EXAMPLE 51 Preparation of ##STR36##

To the title compound of example 8 (520 mg, 1.28 mmol) in 1:4 THF/EtOH(20 ml) was added lithium hydroxide (46 mg (1.92 mmol) in H₂ O (10 ml)and stirred for 2.5 h. The reaction mixture was acidified with 1N HCl topH 3 and concentrated in vacuo. The mixture was purified bychromatography on silica gel (CH₃ OH/HOAc/CH₂ Cl₂ gradient 10/1/89 to20/1/79) to give 124 mg (18%) of the title compound. MS calcd for C₂₁H₁₉ N₃ O₄ : 377, found 377.

EXAMPLE 52 Preparation ofcis-4-[(2-Naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxamide

The product of example 42 is treated with oxalyl chloride and acatalytic amount of DMF in CHCl₃. After 2 h at room temperature thesolution is concentrated in vacuo. The acid chloride is then redissolvedin CHCl₃ and treated with gaseous ammonia. An aqueous workup andpurification via chromatography affords the title compound.

EXAMPLE 53 Preparation of ##STR37##

To the product of Example 42 (100 mg, 0.264 mmol) in DMF (2.5 ml) wasadded 1,1-carbonyldiimidazole (43 mg, 0.264 mmol). After stirring for 3h at room temperature, pyrrolidinone (19 mg, 0.264 mmol) was added andthe reaction was then stirred for 18 h at room temperature. Afterremoval of the solvent in vacuo, a solution of K₂ CO₃ (36 mg) in H₂ O (5ml) was added and the mixture was extracted with CH₂ Cl₂. The CH₂ Cl₂extractions were washed with H₂ O and brine and then dried (MgO₄) andconcentrated to give an oil which was chromatographed on a silica gelchromatotron plate (2 mm) eluting with 5% EtOH/CH₂ Cl₂ to give thediamide title compound (32 mg, 28%). Anal calcd for C₂₆ H₂₄ N₃ O₃.H₂ O:C, 70.10; H, 6.11; N, 9.43. Found: C, 70.27; H, 5.77; N, 9.24. MS calcdfor C₂₆ H₂₄ N₃ O₃ 427, found 427. DSC=208.6°-209.8° C.@96 J/g.

EXAMPLE 54 Preparation of ##STR38##

To a solution of the product of example 30 (103 mg, 0.283 mmol) in DMF(2 ml) was added 1,1-carbonyldiimidazole (46 mg, 0.283 mmol). Afterstirring for 5.5 h, pyrrolidine (0.05 ml, 0.566 mmol) was added and thereaction was stirred for 18 h. The resulting precipitate was filteredand then worked with CH₃ OH to give 91 mg (77%) of the title compound.MS calcd for C₂₄ H₂₄ N₄ O₃ : 416, found 416. DSC=218.72°-234.43° C.

EXAMPLE 55 Preparation of ##STR39##

To a solution of the product of Example 41 (Compound B) (106 mg, 0.28mmol) in DMF (2 ml) was added 1,1-carbonyldiimidazole (45 mg, 0.28mmol). After stirring for 5 h, pyrrolidine (0.23 ml, 2.8 mmol) was addedand the reaction was stirred for 48 h at room temperature. Evaporationof the solvent in vacuo gave a yellow oil which was purified by radialchromatography (silica gel, 2 mm plate) eluting with 3% EtOH/CH₂ Cl₂ togive the title diamide compound (80 mg, 67%). Anal calcd for C₂₆ H₂₄ N₃O₃.1/2H₂ O: C, 71.54; H, 6.00; N, 9.62. Found: C, 71.38; H, 6.08; N,9.31. MS calcd for C₂₆ H₂₄ N₃ O₃ 427, found 427. DSC=206.8°-208.1°C.@79.9 J/g.

EXAMPLE 56 Preparation oftrans-4-[(2-Naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxamide

The trans-product of example 41 is converted to the correspondingprimary amide via the acid chloride as described for example 52.

EXAMPLE 57 Preparation of ##STR40##

To a solution of the aminopyrrolidinone (150 mg, 5.43 mmol) of Example Vand triethylamine (0.15 ml, 10.9 mmol) in CH₂ Cl₂ (2 ml) was added3,4-dichlorophenylsulfonyl chloride (133 mg 5.43 mmol). The reaction wasthen stirred for 18 h at room temperature after which time the solventwas evaporated. The residue was chromatographed on silica gel elutingwith EtOH/CH₂ H₂ (3/97) to give the desired title sulfonamide, 180 mg(73%). Anal. calcd. for C₂₁ H₂₂ N₂ O₅ Cl₂ S: C,51.97; H,4.57; N,5.77.Found C,51.50; H,4.61; N,5.58. MS calcd. for: C₂₁ H₂₂ N₂ O₅ Cl₂ S 585,Found 484.

EXAMPLE 58 Preparation of 1,1-dimethylethylcis-4-[(2-naphthalenylsulfonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate##STR41##

To a solution of 2-naphthalene sulfonylchloride (0.238 mg, 1.05 mmol) inCH₂ Cl₂ (2 ml) was added a solution of the aminopyrrolidinone of ExampleV (0.290 mg, 1.05 mmol) and triethylamine (0.15 ml, 1.05 mmol) in CH₂Cl₂ (3 ml) and stirred for 18 h. The desired solid was then filtered.The filtrate was purified by radial chromatography (2% EtOH/CH₂ H₂) togive additional desired material. Recrystallization of the combinedsolids from CH₂ Cl₂ afforded the title compound (375 mg, 80%). Anal.calcd. for C₂₅ H₂₆ N₂ O₅ S.1/3H₂ O: C, 63.54; H, 5.69; N, 5.93. Found:C, 63.86; H, 5.69; N, 5.71. DSC=192.01°-194.52° C. at 73.88 J/g.

EXAMPLE 59 Preparation of ##STR42##

The title compound of Example 57 (140 mg, 0.288 mmol) was dissolved intrifluoroacetic acid (2 ml) and stirred for 3.5 h at room temperatureafter which time the reaction was concentrated in vacuo. Resuspension ofthe residue in CH₂ Cl₂ and filtration gave 84 mg (68%) of the titlecompound as a solid. Anal. calcd. for C₁₇ H₁₄ N₂ SO₅ Cl₂ :, C, 47.547;H, 3.29; N, 6.53. Found: C, 47.26; H, 3.25; N, 6.49. MS calcd. for C₁₇H₁₄ N₂ SO₅ Cl₂ 430, found 430. DSC=168.46° C. at 32.01 J/g and 174.86°C. at 30.17 J/g.

EXAMPLE 60 ##STR43##

The tert-butyl ester of example 58 (320 mg, 0.686 mmol) was dissolvedtriflouroacetic acid (2 ml) and stirred for 2.5 h after which time thereaction was concentrated in vacuo. The resulting material wasrecrystallized from CH₂ Cl₂ /CH₃ OH to give 116 mg (41%) of the titlecompound as a white solid. Anal. Calcd. for C₂₁ H₁₈ N₂ O₅ S.1/4H₂ O:C,60.79; H,4.49; N,6.75. Found: C,60.94; H,4.45; N,6.71. MS calc for C₂₁H₁₈ N₂ O₅ S 410, found 410. DSC=221.0°-224.1° C. at 109.2 J/g.

EXAMPLE 61 Preparation of 1-Phenyl-2,3-pyrrolidinedione

According to the procedure of Southwick [J. Org. Chem. 21, 1087(1956)]the ethyl ester pyrrolidinone of Example S (1.0 g, 4.0 mmol) wassuspended in 75 ml of 20% HCl/H₂ O and refluxed for 3.5 h The reactionwas cooled and filtered and the filtrate was extracted with CHCl₃ (4×150ml). Concentration of the combined extracts gave an off-white solid (358mg). 'NMR(300 MHZ, CDCl₃) δ2.92 (t, 2H), 4.17 (t, 2H), 7.32 (t, 1H),7.98 (t, 2H), 7.84 (d, 2H).

EXAMPLE 62 Preparation of Ethyl 4,5-dioxo-1-phenyl-3-pyrrolidineacetate

A solution of the product of Example 61 in THF is added to a solution oflithium di-iso-propylamide (LDA) in THF at -78° C. After 2 h at -78° C.a solution of ethyl bromoacetate is added and the reaction is allowed towarm to room temperature. After an aqueous workup the crude product ischromatographed on silica gel to give the title compound.

EXAMPLE 63 Preparation of Ethyl4-(hydroxyimino)-5-oxo-1-phenyl-3-pyrrolidineacetate

A solution of product of Example 62 in pyridine is treated with anexcess of hydroxylamine hydrochloride and the reaction is stirred atroom temperature for 2 d. The solution is concentrated in vacuo and theresidue is chromatographed on silica gel to give the title compound.

EXAMPLE 64 Preparation of Ethyl4-amino-5-oxo-1-phenyl-3-pyrrolidineacetate

A solution of the product of example 63 in EtOH is hydrogenated with 10%palladium on carbon at 60 psi at 60° C. Filtration and purification ofthe product on silica gel affords the title compound.

EXAMPLE 65 Preparation ofcis-4-[(1H-Indol-2-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidineaceticacid

The aminopyrrolidinone of Example 63 is coupled with indole-2-carboxylicacid according to the procedure described in Example 4 and the resultingester is saponified to give the title homologated acid.

EXAMPLE 66 Preparation of3-[[2-(Methoxymethyl)-1-pyrrolidinyl]imino]-1-phenyl-2-pyrrolidinone

A solution of the product of Example 61 and chiral1-amino-2-methoxymethylpyrrolidine (SAMP or RAMP; 1 equiv) in benzene isrefluxed under Dean-Stark conditions for 20 h After cooling, Et₂ O isadded and the mixture is washed with water. The organic layer is dried(MgO₄), and evaporated to give a residue which is chromatographed onsilica gel to give the title compound.

EXAMPLE 67 Preparation of Ethyl4-[[2-(methoxymethyl)-1-pyrrolidinyl]imino]-1-phenyl-5-oxo-3-pyrrolidineacetate

To a solution of SAMP hydrazone of Example 66 or RAMP hydrazone ofExample 66 in anhydrous THF at -78° C. is added dropwise a solution oftert-butyllithium (1.1 equiv) in n-hexane and the mixture is stirred for2 h at -78° C. The solution of metalated hydrazone is cooled to -100° C.and a solution of ethyl bromoacetate (1.2 equiv) in anhydrous THF isadded dropwise and the mixture is stirred for 1 h at -100° C. and thenwarmed slowly to room temperature over 15 h Finally, Et₂ O is added andthe mixture is washed with pH7-buffer and brine, dried (MgO₄), andevaporated under reduced pressure to give a residue which ischromatographed on silica gel eluting with EtOH/CH₂ Cl₂ to give thetitle alkylated hydrazone in high diastereomeric excess.

EXAMPLE 68 Preparation of enantiomerically pure Ethylcis-4-amino-5-oxo-1-phenyl-3-pyrrolidineacetate

A solution of SAMP hydrazone of Example 67 or the RAMP hydrazone ofExample 67 in EtOH is hydrogenated with 10% palladium on carbon at 1200psi at 70° C. for 24 h Filtration and evaporation of the filtrate givesa residue which is chromatographed on silica gel eluting with 2%EtOH/CH₂ Cl₂ to give the desired title compound. Alternatively thehydrazone of Example 67 in anhydrous THF is treated with catecholboranefollowed by treatment with Raney Nickel. Filtration and evaporation ofthe filtrate gives a residue which is chromatographed on silica gel togive the title compound.

EXAMPLE 69 Preparation of enantiomerically purecis-4-[(1H-Indol-2-ylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidineaceticacid

To a solution of indole-2-carboxylic acid in DMF is added 1 equivalentof 1,1-carbonyldiimidazole. After stirring for 4 h at room temperature asolution of the aminopyrrolidinone of Example 68 in DMF is added. Afterstirring for 12 h at room temperature the reaction mixture is evaporatedin vacuo to give a residue which is chromatographed on silica gel togive the desired amide. To a solution of the amide in 1:4 EtOH/THF isadded a solution of lithium hydroxide (11.4 equiv) in H₂ O and theresulting solution is stirred for 2 h at room temperature. The reactionmixture is then acidified to pH=2 with 1N HCl. Removal of the solventgives a residue which is chromatographed on silica gel to give the titlecarboxylic acid as a single enantiomer.

EXAMPLE 70 Preparation ofcis-N-(p-Methoxyphenyl)-3-carboxy-4-(1H-indol-2'-ylcarbonyl)aminoazetidin-2-one ##STR44##

Cis-N-(p-methoxyphenyl)3-carboxy-4-dibenzylaminoazetidin-2-one t-butylester (T. Hiyama et al., J. Amer. Chem. Soc. (1989), 111, 6843) ishydrogenolyzed with 10% Pd-C/ammonium formate to affordcis-N-(p-methoxyphenyl)-3-carboxy-4-aminoazetidin-2-one t-butyl ester,which is not isolated but reacted directly with indole-2-carboxylicacid-carbonyldiimidazole/THF to givecis-N-(p-methoxyphenyl)-3-carboxy-4-(1H-indol-2'-yl)aminoazetidin-2-onet-butyl ester. Removal of the t-butyl ester with trifluoroacetic acidaffords the title compound.

EXAMPLE 71 Preparation oftrans-N-(p-Methoxyphenyl)-3-carboxy-4-(1H-indol-2'-ylcarbonyl)aminozetidin-2-one ##STR45##

Following the procedure of Example 70,trans-N-(p-methoxyphenyl)-3-carboxy-4-dibenzylaminoazetidin-2-onet-butyl ester (T. Hiyama et al., J. Amer. Chem. Soc. (1989), 111, 6843)is converted to the title compound.

EXAMPLE 72 Preparation ofcis-N-(1'-Phenylethyl)-3-carboxy-4-(1H-indol-2"-ylcarbonyl)aminoazetidin-2-one##STR46##

Following the procedure of Example 70,cis-N-(1'-phenylethyl)-3-carboxy-4-dibenzylaminoazetidin-2-one t-butylester (T. Hiyama et al., J. Amer. Chem. Soc. (1989), 111, 6843) isconverted to the title compound.

EXAMPLE 73 Preparation oftrans-N-(1'-Phenylethyl)-3-carboxy-4-(1H-indol-2"-ylcarbonyl)aminoazetidin-2-one##STR47##

Following the procedure of Example 70,trans-N-(1'-phenylethyl)-3-carboxy-4-dibenzylaminoazetidin-2-one t-butylester (T. Hiyama et al., J. Amer. Chem. Soc. (1989), 111, 6843) isconverted to the title compound.

EXAMPLE 74

Percent displacement of ¹²⁵ I-CCK-OP binding to rat pancreatic membraneand guinea pig brain homogenates by compounds of the instant inventionat different concentrations was used to quantify CCK-A and CCK-Breceptor binding, respectively.

Binding of 125-CCK-OP to rat pancreas (CCK-A) and guinea pig brain(CCK-B) homogenates.

Rat pancreas or guinea pig brain was homogenized in 50 and 20 volumes,respectively, of 50 mM Tris-HCl buffer (pH 7.8 at 25° C.) with aBrinkmann polytron homogenizer. The homogenates were centrifuged twiceat 50,000×g for 20 min with an intermediate rehomogenization in freshbuffer. The final pellets were resuspended in 20 volumes (brain) or 40volumes (pancreas) of incubation buffer [50 mM Tris-HCl, 5 mM MgCl₂,0.2% BSA, 5 mM dithiothreitol, 0.14 mg/ml bacitracin, pH 7.9 at 25° C.].One milliliter of the final homogenate from brain or pancreas wasdiluted to 50 mL with incubation buffer to use in the binding assay.

Binding experiments were performed in a final volume of 1 mL in 13×100mm borosilicate disposable culture tubes. To duplicate tubes were added890 μL of freshly resuspended pancreas or brain homogenate; 73,000 dpmof ¹²⁵ I-CCK-OP (final concentration, 12 pM) and 10 μL of DMSOcontaining displacing agents (compounds or reference compounds, at thedesired final concentrations). Nonspecific (nonsaturable) binding wasdetermined in the presence of 1 μM unlabeled CCK-OP. After incubationfor 30 min at 37° C. the binding was stopped by rapid filtration under areduced pressure through glass fiber FPD-105 Whatman GF/B filters onHarvester and washed twice with 5 mL of ice-cold Tris buffer (50 mMTris-HCl, pH 7.8). The radioactivity on the filters was counted in agama counter. Radioactivity adsorbed to filters (filter blanks) was lessthan 0.5% of total radioactivity and was not displaced by the additionof unlabeled CCK-OP. Specific binding was defined as the excess bindingover that in blanks containing 1 μM unlabeled CCK-OP.

Determination of IC₅₀ for Displacing Agents

The ability of compounds to displace ¹²⁵ I-CCK-OP binding to pancreaticor brain membrane homogenate was assessed in duplicate at concentrationsvarying from 10⁻⁵ M to 10⁻⁷ M. When the percent inhibition of specific¹²⁵ I-CCK-OP binding by the displacing agent at the highest screeningconcentration was ≧50%, the compound was considered as active and anIC₅₀ value was determined. The IC₅₀, the concentration of compound thatinhibits 50% of specific ¹²⁵ I-CCK-OP binding, was estimatedgraphically.

Rat Gastric Emptying Protocol

A test meal for measuring gastric emptying in rats was prepared. Tengrams of methylcellulose (2% solution=15 centipoises; Aldrich ChemicalCompany, Milwaukee, Wis. was added to 200 ml of cold water and mixed at20,000 rpm in a Waring blender to insure dispersion and hydration of themethylcellulose. In addition, two beef bouillon cubes (Wyler's,Columbus, Ohio) dissolved in 100 ml of warm water was added to themixture, followed by 16 g of casein (Hammersten, Schwartz/Mann,Orangeburg, N.Y.), 8 g of powdered confectioners sugar and 8 g ofcornstarch. The ingredients were mixed for two minutes at 20,000 rpm andthe resultant test meal was refrigerated for 48 hours to allow trappedair to escape. Male Charles River Rats, Crl: COBS, CD (SD) BR Strain,180-200 g body weight, were used in groups of six animals. The animalswere food deprived for 24 hours prior to the experiment with access towater ad libitum. The compounds to be evaluated were prepared in a 0.5%aqueous methylcellulose solution. If insoluble, the mixture washomogenized for two minutes at 5500 rpm using a Try-R-Stir-R. Thecompounds were given intraperitoneally or intragastrically at a volumeof 5 ml/kg, 60 minutes or 90 min, respectively, before the test meal.Control animals received only the vehicle. Cholecystokinin (100 μg/Kg,i.p.) was given 30 minutes before the test meal to delay gastricemptying by an effect elicited through CCK receptors. Sixty minutesafter the test meal (2.0 ml/rat, i.g.), the rats were sacrificed by CO₂asphyxiation. The stomachs were removed intact and weighed. The stomachswere kept opened, gently rinsed with tap water, blotted dry with papertoweling, and the empty stomach weighed. The difference between theweight of the full and empty stomach is indicative of the amount of mealremaining in the stomach. The amount of meal remaining in the stomachwas subtracted from the weight of 3 ml of the test meal to determine theamount of food emptied from the stomach during the test. Weight of thetest meal was determined by weighing three samples (3 ml) at thebeginning and three samples at the end of each experiment andcalculating the mean. The mean and standard error of the amount of mealemptied were calculated for at least 5 doses of compound, and expressedas percent change from control. Statistical testing was done for eachdose of compound and an ED₅₀ value was estimated if significant (p<0.05)activity was observed at any dose.

The results of the above protocols for a representative number ofcompounds of the present invention are shown in Table B.

                                      TABLE B                                     __________________________________________________________________________                      CCK-A BINDING       CCK-DELAYED                                               RAT       CCK-B BINDING                                                                           GASTRIC                                                   PANCREATIC                                                                              GP BRAIN  EMPTYING:                               Example           MEMBRANES:                                                                              MEMBRANES:                                                                              ED.sub.50 or %                          #    COMPOUND     IC50 (uM) IC50 (uM) Reversal @ Dose                         __________________________________________________________________________    41   cis-4-[(2-   0.015     48% @ 10  ED50 = 0.41 mpk                              naphthalenylcarbonyl)            IP                                           amino]-5-oxo-1-phenyl-                                                        3-pyrrolidinecarboxylic                                                       acid                                                                     41   trans-4-[(2- 0.29      22% @ 10  ED50 = 3.2 mpk                               naphthalenylcarbonyl)            IP                                           amino]-5-oxo-1-phenyl-                                                        3-pyrrolidinecarboxylic                                                       acid                                                                     44   cis-1-(2-fluorophenyl)-                                                                    0.062     41% @ 10  86% @ 3 mpk IP                               4-[(2-                           ED.sub.50 = 1.7 mpk                          naphthalenylcarbonyl]            IP                                           amino]-5-oxo-3-                                                               pyrrolidinecarboxylic                                                         acid                                                                     39   trans-4-[(2- >10       --                                                     naphthalenylcarbonyl]                                                         amino-5-oxo-1-pentyl-3-                                                       pyrrolidinecarboxylic                                                         acid                                                                     28   cis-1-(2-fluorophenyl)-                                                                    0.17      >10                                                    5-oxo-4-[(3-                                                                  quinolinylcarbonyl)                                                           amino]-5-oxo-3-                                                               pyrrolidinecarboxylic                                                         acid                                                                     27   cis-5-oxo-1-pentyl-4-                                                                      0.25      >10                                                    [(3-quinolinylcarbonyl)                                                       amino]-3-                                                                     pyrrolidinecarboxylic                                                         acid, monohydrochloride                                                  29   cis-4-[(1-H-indol-2-                                                                       0.017     5.1       86.3% @ 1.0 mpk                              ylcarbonyl)amino]-5-             IP                                           oxo-1-phenyl-3-                  ED.sub.50 < 0.1 mpk                          ppyrrolidinecarboxylic           IP                                           acid                                                                     30   trans-4-[(1H-indol-2-                                                                      0.32      --                                                     ylcarbonyl)amino]-5-                                                          oxo-1-phenyl-3-                                                               pyrrolidinecarboxylic                                                         acid                                                                     35   cis-4-[[(3,4-                                                                              0.058     35% @ 10  57.9% @ 3.0 mpk                         (cis)                                                                              dichlorophenyl)                                                               carbonyl]amino]-5-oxo-                                                        1-phenyl-3-                                                                   pyrrolidinecarboxylic                                                         acid                                                                     35   trans-4-[[(3,4-                                                                            >1.0      >10                                               (trans)                                                                            dichlorophenyl)                                                               carbonyl]amino]-5-oxo-                                                   1-phenyl-3-                                                                        pyrrolidinecarboxylic                                                         acid                                                                     32   cis-4-[[(3,4-                                                                              0.3       49% @ 10                                               dichlorophenyl)                                                               carbonyl]amino]-5-oxo-                                                        1-pentyl-3-                                                                   pyrrolidinecarboxylic                                                         acid                                                                     46   cis-4-[[(4-  1.6       >10                                               (cis)                                                                              chlorophenyl)carbonyl]                                                        amino]-5-oxo-1-phenyl-                                                        3-pyrrolidinecarboxylic                                                       acid                                                                     46   cis-4-[[(4-  41        >10                                               (trans)                                                                            chlorophenyl)carbonyl]                                                        amino]-5-oxo-1-phenyl-                                                        3-pyrrolidinecarboxylic                                                       acid                                                                     45   trans-4-[[(4-                                                                              >1.0      >10                                                    chlorophenyl)carbonyl]                                                        amino]-5-oxo-1-pentyl-                                                        3-pyrrolidinecarboxylic                                                       acid                                                                     40   cis-4-[[(2-  2.8       3.9                                                    naphthalenylamino)                                                            carbonyl]amino]-5-oxo-                                                        1-pentyl-3-                                                                   pyrrolidinecarboxylic                                                         acid                                                                     36   cis-4-[[[(3,4-                                                                             0.10      10.0                                              (cis)                                                                              dichlorophenyl)amino]                                                         carbonyl]amino]-5-oxo-                                                        1-phenyl-3-                                                                   pyrrolidinecarboxylic                                                         acid                                                                     36   trans-4-[[[(3,4-                                                                           >1.0      45% @ 10                                          (trans)                                                                            dichlorophenyl)amino]                                                         carbonyl]amino-5-oxo-1-                                                       phenyl-3-                                                                     pyrrolidinecarboxylic                                                         acid                                                                     34   cis-4-[[[(3,4-                                                                             0.35      6.0                                                    dichlorophenyl)amino]                                                         carbonyl]amino]-5-oxo-                                                        1-pentyl-3-                                                                   pyrrolidinecarboxylic                                                         acid                                                                     47   trans-4-[[[(4-                                                                             >1.0      --                                                     chlorophenyl)amino]                                                           carbonyl]amino]-5-oxo-                                                        1-pentyl-3-                                                                   pyrrolidinecarboxylic                                                         acid                                                                     47   cis-4-[[[(4- >1.0                                                             chlorophenyl)amino]                                                           carbonyl]amino]-5-oxo-                                                        1-pentyl-3-                                                                   pyrrolidinecarboxylic                                                         acid                                                                     51   trans-4-[(3- >1.0      >10.0                                                  indolyacetyl)amino]-5-                                                        oxo-1-phenyl-3-                                                               pyrrolidinecarboxylic                                                         acid                                                                          1,1-dimethylethyl cis-                                                                     32% @ 1.0 35% @ 10                                               4-[(2-                                                                        naphthalenylcarbonyl)am                                                       ino]-5-oxo-1-phenyl-3-                                                        pyrrolidinecarboxylate                                                   53   cis-1-[[3-[(2-                                                                             0.75      45% @ 10                                               naphthalenylcarbonyl)am                                                       ino]-2-oxo-1-phenyl-4-                                                        pyrrolidinyl]carbonyl]                                                        pyrrolidine                                                              55   trans-1-[[3-[(2-                                                                           27% @ 1.0 10.0                                                   naphthalenylcarbonyl)am                                                       ino]-2-oxo-1-phenyl-4-                                                        pyrrolidinyl]carbonyl]                                                        pyrrolidine                                                              __________________________________________________________________________

What we claim is:
 1. A compound according to claim 1 having the formula##STR48## and isomer thereof; or a pharmaceutically acceptable acid orbase addition salt thereof:wherein Ar isaryl; substituted aryl which canbe substituted one or more by alkyl of 1 to 6 carbon atoms, alkoxywherein the alkyl is 1 to 6 carbon atoms, trifluoromethyl, halogen,amino, alkyl or dialkyl substituted amino wherein the alkyl is 1 to 6carbon atoms; fused bicyclic aromatic hydrocarbon radical having 9 or 10carbon atoms; substituted fused bicyclic aromatic hydrocarbon radicalhaving 9 or 10 carbon atoms which can be substituted one or more byalkyl of 1 to 6 carbon atoms, halogen, trifluoromethyl, amino, alkyl ordialkyl substituted amino wherein the alkyl is 1 to 6 carbon atoms oralkoxy wherein the alkyl is 1 to 6 carbon atoms; R isalkyl having 1 to 8carbon atoms wherein one of the carbon atoms may be replaced by oxygen;aryl; substituted aryl which can be substituted one or more by halogen,alkyl having 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6carbon atoms, amino, alkyl or dialkyl substituted amino wherein thealkyl is 1 to 6 carbon atoms, trifluoromethyl or methylene dioxy;aralkyl wherein the alkyl is 1 to 8 carbon atoms; substituted aralkylwherein the alkyl is 1 to 8 carbon atoms and the substituent orsubstituents are selected from the group consisting of halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl or methylene dioxy; X is a directbond or a substituent selected from the group consisting of NH, oxygenor alkylene having 1 to 3 carbon atoms; R₁ and R₁ ' are eachindependently hydrogen or alkyl having 1 to 4 carbon atoms; m is aninteger from 0 to 3; R₃ is OH, OR₅ wherein R₅ is alkyl having 1 to 6carbon atoms or NR₆ R₇ wherein R₆ and R₇ are each independently hydrogenor alkyl of 1 to 6 carbon atoms; R₄ is hydrogen or alkyl having 1 to 4carbon atoms; and Y is C═O.
 2. A compound according to claim 1 havingthe formula ##STR49## and isomers thereof; or a pharmaceuticallyacceptable acid or base addition salt thereof:wherein Ar isaryl;substituted aryl which can be substituted one or more by alkyl of 1 to 6carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, halogen, amino, alkyl or dialkyl substituted aminowherein the alkyl is 1 to 6 carbon atoms; R isalkyl having 1 to 8 carbonatoms wherein one of the carbon atoms may be replaced by oxygen; aryl;substituted aryl which can be substituted one or more by halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl, or methylene dioxy; or aralkylwherein the alkyl is 1 to 8 carbon atoms; R₁ and R₁ ' are eachindependently hydrogen or alkyl having 1 to 4 carbon atoms; m is aninteger from 0 to 3; R₃ is OH or OR₅ wherein R₅ is alkyl having 1 to 6carbon atoms; R₄ is hydrogen; Y is C═O; and X is a direct bond or asubstituent selected from the group consisting of NH, oxygen, oralkylene having 1 to 3 carbon atoms.
 3. A compound according to claim 1having the formula ##STR50## and isomers thereof; or a pharmaceuticallyacceptable acid or base addition salt thereof:wherein Ar is fusedbicyclic aromatic hydrocarbon radical having 9 or 10 carbon atoms;substituted fused bicyclic aromatic hydrogen radical having 9 or 10carbon atoms which can be substituted one or more by alkyl of 1 to 6carbon atoms, halogen, trifluoromethyl, amino, alkyl or dialkylsubstituted amino wherein the alkyl is 1 to 6 carbon atoms, or alkoxywherein the alkyl is 1 to 6 carbon atoms; R isalkyl having 1 to 8 carbonatoms wherein one of the carbon atoms may be replaced by oxygen; aryl;substituted aryl which can be substituted one or more by halogen, alkylhaving 1 to 6 carbon atoms, alkoxy wherein the alkyl is 1 to 6 carbonatoms, amino, alkyl or dialkyl substituted amino wherein the alkyl is 1to 6 carbon atoms, trifluoromethyl or methylene dioxy; aralkyl whereinthe alkyl is 1 to 8 carbon atoms; substituted aralkyl wherein the alkylis 1 to 8 carbon atoms and the substituent or substituents are selectedfrom the group consisting of halogen, alkyl having 1 to 6 carbon atoms,alkoxy wherein the alkyl is 1 to 6 carbon atoms, amino, alkyl or dialkylsubstituted amino wherein the alkyl is 1 to 6 carbon atoms,trifluoromethyl, or methylene dioxy; R₁ and R₁ ' are each independentlyhydrogen or alkyl having 1 to 4 carbon atoms; m is an integer from 0 to3; R₃ is OH, OR₅ wherein R₅ is alkyl having 1 to 6 carbon atoms or NR₆R₇ wherein R₆ and R₇ are each independently hydrogen or alkyl of 1 to 6carbon atoms; R₄ is hydrogen; Y is C═O; and X is a direct bond or asubstituent selected from the group consisting of NH, oxygen or alkylenehaving 1 to 3 carbon atoms.
 4. A compound according to claim 2 which iscis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.
 5. A compound according to claim 2 which istrans-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.
 6. A compound according to claim 2 which iscis-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.
 7. A compound according to claim 2 which iscis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.
 8. A compound according to claim 2 which iscis-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 9. A compound according to claim 2 which istrans-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 10. A compound according to claim 2 which iscis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 11. A compound according to claim 2 which istrans-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 12. A compound according to claim 2 which istrans-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 13. A compound according to claim 2 which iscis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 14. A compound according to claim 3 which istrans-4-[(2-naphthalenylcarbonyl]amino-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.
 15. A compound according to claim 3 which iscis-1-[(2-fluorophenyl)-4-[(2-naphthalenylcarbonyl]amino]-5-oxo-3-pyrrolidinecarboxylicacid.
 16. A compound according to claim 3 which iscis-4-[[(2-naphthalenylamino)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid.
 17. A compound according to claim 3 which iscis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 18. A compound according to claim 3 which istrans-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid.
 19. A compound according to claim 3 which is 1,1-dimethylethylcis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylic.
 20. A compound accordingto claim 1 which iscis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid.
 21. A compound according to claim 1 which iscis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid.
 22. A compound according to claim 1 which iscis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-(methylphenyl)-3-pyrrolidinecarboxylicacid.
 23. A pharmaceutical composition useful for treating andpreventing cholecystokinin related disorders of the gastrointestinal,central nervous and appetite regulatory systems of mammals comprising atherapeutically effective amount of at least one compound according toclaim 1, together with one or more non-toxic pharmaceutically acceptablecarriers.
 24. A pharmaceutical composition according to claim 23 whereinsaid compound is selected from the group consistingofcis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;trans-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;trans-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[[[(4-chlorophenyl)]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[[[(3,4-dichlorophenyl)]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;cis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[[[(3,4-dichlorophenyl)]carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[(2-naphthalenylcarbonyl]amino-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-1-[(2-fluorophenyl)-4-[(2-naphthalenylcarbonyl]amino]-5-oxo-3-pyrrolidinecarboxylicacid;cis-4-[[(2-naphthalenylamino)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;
 1. 1-dimethylethyl cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate;cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid;cis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid; and cis-4-[[[(3,4-dichlorophenyl))amino] carbonyl]amino]-5-oxo-1-(methylphenyl)-3-pyrrolidinecarboxylic acid.
 25. A methodfor treating and preventing cholecystokinin related disorders of thegastrointestinal, central nervous, and appetite regulatory systems ofmammals comprising administering a therapeutically effective dose of atleast one compound of claim 1 to a mammal in need of such treatment. 26.A method according to claim 25 wherein said compound is selected fromthe group consistingofcis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;trans-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;trans-4-[[[(4-chlorophenyl)amino]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[[[(4-chlorophenyl)]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[[[(3,4-dichlorophenyl)]carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[[(4-chlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;cis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[[[(3,4-dichlorophenyl)]carbonyl]amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[(2-naphthalenylcarbonyl]amino-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-1-[(2-fluorophenyl)-4-[(2-naphthalenylcarbonyl]amino]-5-oxo-3-pyrrolidinecarboxylicacid;cis-4-[[(2-naphthalenylamino)carbonyl]amino]-5-oxo-1-pentyl-3-pyrrolidinecarboxylicacid;cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;trans-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylicacid;
 1. 1-dimethylethyl cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-phenyl-3-pyrrolidinecarboxylate;cis-4-[(2-naphthalenylcarbonyl)amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid;cis-4-[[(3,4-dichlorophenyl)carbonyl]amino]-5-oxo-1-(phenylmethyl)-3-pyrrolidinecarboxylicacid; andcis-4-[[[(3,4-dichlorophenyl)amino]carbonyl]amino]-5-oxo-1-(methylphenyl)-3-pyrrolidinecarboxylicacid.